Friday, August 28, 2009

Empty Follicle Syndrome

Sorry for the long question but I wanted to make sure you had a good picture.....
I am 38 year old and have been trying to get pregnant for a while. I got pregnant using clomid and HCH shot but had a pregnancy lost in 2007 at approx 24 weeks. I did a thrombophilia work up and one of my clotting factors was borderline so the action that I was to go on blood thinners with a next pregnancy. High FSH has been a problem as it peaked at 20.23 during one cycle when I was doing the IUIs. I had to date 3 unsuccessful IUIs and two cancelled IVF due to empty follicles. The first IVF cycle I had two follicles after using Lupron in the beginning and then repronex and gonal F for several days and finished with Novarel HCG shot.
The second attempt my RE did a different approach. I was placed on birth control for one cycle and the next cycle I start with clomid and then repronex and gonal followed by ganirelix and the last norvarel shot before retrieval. Note that my FSH was 8.8 but estradiol was high at about 90 so that made my FSH skewed. I had four follicles (the most I had have) and they were all empty. I was concerned that the shot was given properly but my RE said that does not have anything to do with them being empty. After the miscarriage I was always taking baby aspirin but no heparin.
Mentally I am not ready for donor eggs and my husband has flat out said no. I want to exhaust all options before I give up. As you would say, "pull out the full court press". I want to try one more cycle but I have doubts whether I should try again with this RE or try someone else. Can you shed some light on the empty follicle syndrome and if I have a chance? I am so desperate that I am trying acupuncture and herbs while I am on "ovary rest" break.
Hello Patrice from the U.S.,
"Empty follicle" syndrome is a description/name of a condition that is found when no eggs are retrieved from obviously adequate sized follicles. It can occur at any age, but seems to be more prevalent the older one gets. So, a woman in her 40's could still have regular menstrual cycles and ovulation, but no egg will be ovulated so pregnancy does not occur. With IVF, we find this when we go to retrieve and get no eggs back. It is thought that this is the "normal natural condition" in the aging ovary. A woman essentially runs out of eggs. However, that does not seem to be the case in younger woman, since younger women stil have a full complement of eggs. So, "running out of eggs" does not seem to be the whole answer.
I have had several cases of empty follicles in both younger and older women. In the younger patients, I have concluded that they did not get adequate HCG stimulation. Previously I had used a generic HCG and worried that it was not produced properly or suffered some type of inactivation in shipping or storage. I therefore switched to Ovidrel. Since then, the incidence of empty follicles has been resolved except in a couple of exceptions. I had two moderately obese young woman have a very poor retrieval despite lots of follicles (both were PCOD patients). By poor retrieval, I mean that there were either no eggs or we only retrieved 1 or 2 eggs despite 25+ follicles. They had given the Ovidrel as instructed, into there belly. In the subsequent cycle, I had then give it in the back of the arm where there was some fatty tissue but much less than the abdomen. They then had good retrievals. This lead me to suspect that HCG stimulation was the problem, and that the increased fatty layer of the abdomen did not allow adequate absorption of the HCG, therefore the eggs did not release to be retrieved.
In your case, with an elevated FSH level, your age and poor ovarian stimulation, the problem may actually be a lack of eggs. However, you did not mention your weight so you might want to look at that possibility. In addition, you may not be stimulating well if you are not getting a large enough dosage of medication. For example, I use a total of 600IU of gonadotropins in the combination 450IU of Follistim and 150IU of Menopur. Are you using that much? If you are, then the poor stimulation is because of ovarian resistance as manifest by an elevated FSH level.
You certainly have the option of continuing to try with your own eggs if that is your only choice (per your husband) and you can afford continuing to try, AND you doctor agrees to allow you to keep trying. However, based on the cycles you have had, realistically Donor eggs is your best option, and the most cost effective since you would probably get pregnant quickly. Using your own eggs is a long shot.
If you don't think that your doctor is giving you an adequate chance, or being aggressive enough, then you certainly can consider changing doctors. The Doctor-Patient relationship is based on TRUST. If you don't have that trust, then you need to move on. If you trust your doctor's abilities then stick it out, albeit, every clinic and doctor have different protocols and treatments for difficult cases so that must be a consideration as well.
If you were my patient, as I mentioned, I would have you on 450IU follistim/150IU Menopur from the start, Aspirin 81mg per day from the start, Medrol 16mg per day from the start, Heparin 2000U twice per day from the start, Estrogen patches and progesterone from retrieval on and I use Ganerelix once the follicles reach 16 mms, NOT Lupron which will inhibit the ovaries from the start (called the long protocol).

I hope this gives you some information to think about.
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program


  1. Hello dr Ramirez,
    Any suggestions as to why this happened and what better protocol to use. Age 43 , fsh 5.07, lh2.6 estrogen 151pmol/L and free testosterone 0.48 nmol/L amh 5.66 (tested oct 2013)
    ivf #1 21days bcp, 7 days suprecur nasal spray and then 450iu gonal f for 11 days and 250 ovidrel trigger. 14 follicles over 16mm At egg retrieval empty follicle . Blood test immediately after ER showed trigger was in my system but lh was 0.1.

    Ivf #2 same protocol except 450iu menopur for 11 days and 500 ovidrel tigger 10 follicles over 16mm and at egg retrieval only 1 egg.

    Both times on day of trigger estrogen levels have been over 10,000

    I suspect ovidrel as the trigger does not work for me.

    Any suggestions.

    Amy in London uk

    1. Hi. One of the problems with increased reproductive age is that more of your follicles can be empty. Of course it is possible that the HCG is not working correctly but I doubt that is the problem as I have not had any cases of empty follicle syndrome since switching to Ovidrel. From the information you've given me, I think that it is most likely that you've run out of eggs.

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    3. There are many factors that can lead to no eggs. Of course one is the empty follicle syndrome, however, in my experience and that reported, it is sporadic and not something that is repetitive. So I'm a little surprised that it has happened to you so many times. Another cause is a lack of adequate stimulation by HCG, which causes the final egg maturation and release from the follicle wall. That may be the culprit in most cases. Another is triggering too early so that the egg doesn't reach maturation and is not release. That's a doctor timing problem, and the fact that you've had this several times makes me wonder about this possibility. Without reviewing your medical records, I can't give you more specifics that this.

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  2. Hi Dr. Ramirez,

    I am trying to figure out what is going wrong. My first IVF cycle I was given a micro flare hcg when I started the cycle then follistim 300 iu- severely hyperstimmed had 70 plus follicles only 7 were retrieved which resulted in one embryo that ended in chemical preg- Hyperstim was s severe I was hospitalized, drained had brain swelling...switched drs...

    Second failed cycle- had stimmed for 6 1/2 days then triggered had 17 follicles 8 measurable had a 20, 5-19's and 2 18 sized follicles had low dose gonal f 100 iu and 1/2 vial of menopur the last four days of stims. triggered with HCG - Dr said everything looked ready by follicle size - results 9 eggs retrieved only 2 mature. Out of those 2 both fertilized one went to day four other to a perfect quality blast- transferred and BFN.. I really like my second Dr and waiting on opinion but dr recommends donor eggs... I am 29 years old - day 3 FSH is 5.4 LH 12.9 , AMH 11.9 . I am heartbroken at the thought of being so young and donor eggs already being a recommendation Do you have any idea what is going on ? What could be the root cause of my eggs not being mature or "dysmature" at retrieval. Is my LH too high prior to the IVF cycle? would that impact egg quality?- we did the lupron down regulation with Birth control. I just don't understand could my eggs be bad at a young age? I do have PCOS have elevated testosterone. Hoping something will help with egg quality such as metformin? Any input would be greatly appreciated

    1. Hi. I can't say what may have happened because there is no way to know. Based on the measurements, you should have had at least 8 mature eggs retrieved. I'm surprised that there were only two. I wonder if the measurements were a little generous and so the trigger was a day or two early.

      First, at your age, I would NOT proceed to donor eggs. I don't think you need them. You need a good doctor with experience with PCO patients that are ultras sensitive to stimulation and you need to keep trying. Your chances of pregnancy are very high. Your first doctor was incompetent and you risks your life with that one.

      Second, sometimes, even despite a good cycle and perfect looking embryo, IVF can fail. It is not a perfect technology. The last three steps in the reproductive process are still natural steps . . . still in God's hands. Sometimes it takes repetition to be successful.

      Third. the "art" in IVF is determining when to trigger. This is based solely on the doctor. The goal is to maximize the number of mature sized follicles (>15mms) in order to retrieve the maximum number of mature eggs. If you trigger to soon, you may get few mature and a lot of immature eggs. So you can't just go by the lead follicles (biggest few), but have to fine a balance between large ones and small ones. I find it better to sacrifice a few large ones in order to get a higher number of smaller ones to maturity size. I think that is what makes a good IVF doctor.

  3. Hi Dr. Ramirez,

    I am 33 years old and we tried natural cycle ivf last month (November 2014). Day 10 follicle size is about 20+mm with LH 25, estradiol 217. The RE gave Suprecure nasal spray that day and we were asked to come back the next day to do oocyte pick up. Unfortunately, the follicle retrieved is empty.

    What do you think about the protocol they used to us. Does day 11 retrieval too early for me which resulted to empty follicle? And should we proceed to stimulated IVF already since the 1st one was no success of retreiving egg or we can try another natural cycle ivf?

    Our profile: 3 failed IUIs, removed uterine polyps, normal menstrual cycle but always experiencing pain during period, sperm count 20-70 M

    Thank you Doctor, your response will be highly appreciated.

    1. I'm not surprised that nothing was retrieved. The egg is attached to the follicular wall and until it fully matures, which occurs when the HCG trigger is given (or the suprecure in your case), it will be 35-36 hours for the egg to undergo this final step. I guess your doctor assumes that the natural LH surge is occurring and so it will be mature by the next day. Well, that was probably mis-timing.

      That is a problem with "natural IVF". It is less predictable so you have to be prepared that you will miss by either trying to retrieved too soon or missing ovulation. Either of those could have been the case with you. Timing of the retrieval or trigger is based on the size of the follicle and not the cycle day. The size of the follicle was certainly appropriate to trigger.

      I do not use natural IVF because I don't like the unpredictability. IVF is way too expensive to risk these simple failures. I am NOT a fan of natural cycle IVF.



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