Case Study: Poor Quality Eggs/Embryos in Young Women With Normal Ovarian Reserve: Case #1 – Polycystic Ovarian Syndrome

02 Nov
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After contemplating how to make my blog posts more helpful to patients with unexplained IVF failures, I have decided to profile the case histories of a number of patients who sought my input after having failed at IVF (often repeatedly). I will try to identify the various potentially remediable reasons for failure, and then make specific recommendations as to how I personally would address (or have addressed) these issues. In some cases, the patients underwent subsequent treatment with me, in which case I have indicated the details and outcome of their treatment.

To make this exercise useful, I have decided to discuss these cases in specific categories that will highlight often overlooked factors that can lead to (unnecessary) IVF failure.

Cases will be presented in three categories:

  1. Women who ended up with poor quality eggs/embryos.
    a. Younger women with normal or exaggerated ovarian reserve
    b. Older women (over age 39) with normal and/or diminished ovarian reserve (DOR)
  2. Women who failed to conceive because of embryo implantation dysfunction
  3. IVF failures following third party IVF (Egg Donation and Gestational Surrogacy)

Please note that the case reports and commentaries will include links to other articles on this site that will hopefully expand on the explanations given.

The first three posts in this series will address Category 1.a – younger women who ended up with poor quality eggs/embryos.

Today’s post profiles a patient with Polycystic Ovarian Syndrome (PCOS) and the various effects of this condition (along with the prescribed IVF protocols) on egg/embryo quality. Friday’s post will discuss a case in which poor egg/embryo quality was due to an occult male factor infertility issue. Next Tuesday I will post case #3, which will detail a patient with poor egg/embryo quality due to advanced endometriosis.

In coming weeks, I will address more cases under the current heading and will then go on to cases involving the other categories listed above.

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Case History #1

“Ann” aged 34 years had been trying to conceive for 3 years. She had never conceived previously (Primary Infertility) in spite of having a fertile male partner, undergoing four attempts at intrauterine insemination using clomiphene citrate (Serophene) for induction of ovulation, and 2 prior IVF procedures. Her menstrual periods were grossly irregular with cycles ranging from 20–35 days apart. Her day-3 blood hormone levels were as follows: Follicle Stimulating Hormone (FSH): 4.5 MIU/ml; Luteinizing Hormone (LH): 9.1 MIU/ml; Estradiol (E2): 62pg/ml; Antimullerian Hormone (AMH): 5.6

Ann had been diagnosed with Polycystic Ovarian Syndrome (PCOS). Both of her IVF treatment cycles (prior to consulting with me) involved ovarian stimulation with Menopur and Ganirelix (beginning on day 6 of stimulation). By the time of the hCG trigger (7-8 days after stimulation started) most of her 40+ follicles were still somewhat under-developed measuring 15-17mm in mean diameter, having not yet attained optimal size (18-22mm), and her peak blood [E2] exceeded 6,000 pg/ml. She was told that she needed to be triggered with hCG at that time to stop the process of follicle growth, which would prevent her blood [E2] from spiraling out of control and potentially causing her to develop the life-endangering condition of Severe Ovarian Hyperstimulation Syndrome (OHSS). In both of these prior cycles, only about 40% of the follicles yielded eggs at the time of egg retrieval. Many of her eggs were immature (MI’s), and those that were mature (MII’s), yielded poor quality embryos after fertilization by ICSI.

She had developed moderately severe ovarian hyperstimulation (abdominal fluid collection, backache and some difficulty in breathing) prior to the embryo transfer (ET), which in both cycles involved the transfer of three (3) day-3, poor quality embryos to her uterus. She did not conceive, but her ovarian hyperstimulation got worse in the ensuing days. She experienced a reduction in urine output, diarrhea, worsening abdominal pain, and progressively more difficult breathing. These symptoms and signs, along with abnormal blood tests pointed to OHSS, which is a life-threatening condition, which fortunately, in the absence of pregnancy is self-limiting and disappears 10-14 days after the hCG shot. Thus, since she did not conceive, she recovered about 10 days later.

Commentary
In my opinion, the reason for the poor egg/embryo quality in these two IVF cycles preceding her final attempt with us, was likely due to the IVF stimulation protocol that was used, as well as premature timing of the hCG trigger. In my experience, women with elevated basal blood [LH] do poorly on protocols that do not down-regulate the LH before and during the stimulation cycle (women with PCOS commonly have elevated blood [LH]). Since the “antagonist” (Ganirelix) was only commenced six days after the stimulation was initiated with Menopur, by the time it suppressed her high pituitary LH production, her eggs had already been exposed to excessive LH-induced ovarian male hormones or androgens (mainly testosterone). It was probably this that had a deleterious effect on her developing eggs and subsequently on her embryo quality.

In addition, because her eggs developed poorly, many of them remained firmly attached to the inner walls of her follicles and could not be retrieved. This would serve to explain why she had so many “empty follicles”. It also probably explains the low percentage of mature (MII) eggs produced in prior cycles and her subsequent poor quality embryos that ultimately led to failed IVF. In addition, Menopur (which aside from FSH also contains 50% LH/hCG) was not the ideal gonadotropin to use in this case, because the additional LH would simply add more “fuel to the fire”.

Another factor here is that the hCG trigger was administered relatively early in her cycle, such that her follicles did not have sufficient time to develop optimally before the process of development was abruptly arrested by the trigger. This was clearly done deliberately in an attempt to reduce the risk of OHSS developing…unsuccessfully in this case.

Follow up
The patient subsequently went through a cycle of COS with me. We prepared Ann for an IVF cycle by starting her on a birth control pill and thereupon, given that she was a “high responder,” we put her on a low-dosage, long pituitary down-regulation protocol with Follistim and Luveris to properly maintain a low LH. She produced 47 follicles which by day 8 of stimulation were (14m-16mm) and her [E2] was 2700pg/ml. At this point I commenced the “prolonged coasting” process by discontinuing the gonadotropins while maintaining the daily “agonist” (Lupron) injections. This would give her follicles and eggs an opportunity to develop optimally (18-22mm) before administering the hCG trigger. Her blood [E2] rose and peaked at 7700pg/ml by day 9 and then began to fall, reaching below 2,500pg threshold by day 12. At this point the follicles were mostly 18-22mm in mean diameter and I administered 10,000U of hCG (Profasi) to trigger ovulation. We retrieved 42 eggs, 34 of which were mature (MII’s) and were fertilized using ICSI. Thirty-one (31) MII’s fertilized and by day-3 post-ICSI, most were 6-9 cells. By day-6, we counted 11 expanded blastocysts and transferred two of these into her uterus. She conceived with a singleton and at this time is nearing the end of the 1st trimester and is doing well. This treatment approach likely prevented OHSS and helped optimize embryo quality.

Addendum:It is important to understand that IVF is an ART-Science blend and not all practitioners agree on the same strategies.Thus, in the final analysis, it is important, after discussion with your personal doctor, to follow his/her advice to the letter.Feel free to present your case history in the comments and I will do my best to offer my opinion.

88 Comments

  • Laura says:

    Hi Dr. Sher,

    I am 33 years old and was dx with “thin” PCOS 2 years ago. We had one natural pregnancy that was an early miscarriage shortly after being put on Metformin for PCOS. Since that time we had 5 failed IUIs and just completed a “mini” IVF that failed to produce a good quality day 5 embryo. Three of eight fertilized naturally, but then none of the three made it (1 made it to a poor grade blastocyst). My doctor’s protocol is this: Birth control for 2 weeks, then 10 IUs of Lupron to down-regulate, also for 2 weeks overlapping w/BCP for a few days. After a baseline u/s to confirm no cysts, etc., stimulation treatment began which included low dose Follistm+Menopur and additionally I continued 5 IUs of Lupron throughout stim treatment. After 10 days of stimulation my follicle growth was good with many in the 18-20mm range; I triggered with pregnyl HCG and egg retrieval was successful with 22 eggs. For this first try, my husband and I opted to only attempt fertilization on 8 eggs….thus they “selected” the best looking 8 and attempted natural fertilization. As I said, 3 of 8 fertilized, the other 5 were immature. My doc believes my % mature eggs is likely lower than normal (due to PCOS?) and that in the next IVF treatment, the protocol should be identical but we need to fertilize more eggs, possibly all of them. We had reduced the quantity because we do not want to produce more than 3-4 viable embryos to use/freeze, so we were trying to minimize by reducing that quantity. What is your advice for me, and is this protocol sound acceptable given my history and all? We have no male factor issues but have been told to consider ICSI to improve fertilization rates. Thanks.

    • Geoffrey Sher says:

      Hi Laura,

      By and large, I have no problem with the protocol you were on, provided the truigger shot involved giving 10000U of hCGu ((pregnyl/profasi/Novarel)or no less rthan 500mcg of hCGr (Ovidrel).I would also suggest that you be assessed for an implantation dysfunction (anatomical or immunologic)…see below.

      Please go to the home page of this blog, http://www.IVFauthority.com . When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.

      1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      2. Ovarian Stimulation for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      3. “Agonist/Antagonist Conversion Protocol”

      4. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.

      5. “Thyroid Autoimmune Disease and IVF”

      6. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)

      7. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)

      8.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      9. “IVF success: Factors that influence outcome”

      10. “Use of the Birth Control Pill in IVF”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization, the ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

      • Laura says:

        Thanks Dr. Sher,
        I read the article you suggested on the autoimmune implantation dysfunction but did not follow it completely, as far as what testing should be conducted. What testing should I ask my doctor to do? I have no other diagnosis or issues other than PCOS, and do not have family history of autoimmune diseases – why do you think this testing would be worthwhile for me? Has autoimmune implantation dysfunction been seen in PCOS patients in your experience?

        Also, my miscarriage 2 years ago occurred on a cycle when I did not ovulate until cycle day 34 which was the latest I had ever ovulated. My cycles were about 40 days when not on fertility drugs, 30-32 when on treatment. The miscarriage occurred at about 8 weeks, but HCG was never doubling.

      • Laura says:

        Hi Dr. Sher – can you tell me more about why you think autoimmune implantation dysfunction and what testing I should specifically ask my doctor for? I did read your articles and somewhat understand, but do you think I’d have this coupled with PCOS? There is no family history of autoimmune diseases and I have not been dx’ed with anything except PCOS (no endometriosis symptoms). The one miscarriage we had was after a very long cycle – I ovulated on day 34 which was the latest ever – and thus we were very shocked to turn up pregnant. However the miscarriage was at 8wks, after HCG never really doubled properly.

        Please let me know what type of testing I could request for an autoimmune implantation dysfunction. Thank you.

        • Geoffrey Sher says:

          Yes Laura…both can occur concommitantly and in fact, they quite often do.

          However, an in depth discussion on testing for, and treating IID will require that we talk. I suggest you call 800-780-7437 and set up a Skype consultation.

          Geoff sher

  • LIT says:

    Dr. Sher,

    My first IVF cycle I hyperstimulation and was on Gonal F and Lupron. They coasted me and I had 15 eggs, 11 fertilize and 1 8 cell and 2 6 cell transferred on day 3 since they were afraid none would make it to blast. Unsuccessful. I switched Dr’s and the new protocol was, metfotmin, Menopur, Follistim, Ganirelix with a lupron trigger. Goal was freeze and do a FET. 1st cycle over 20 eggs, 18 fertilized…several blasts but only two were good enough to freeze. Second cycle same protocol and only 1 “borderline” blast made it to freeze. The two good ones ended in a miscarriage after FET. My GTT was normal, Hbg A1c was 5.0, and all other tests FSH, LH, testosterone, DHEA were normal. Amh 7.5, TSH 1.3. Long menstrual cycles 35-38 days and mild hair on chin. They did not see any signs of PCOS on sonogram. But believe I have it do to hyperstimulation. Can this be? Is the lupron trigger the best protocol for this? I also have factor V Leiden homozygous and MTHFR Herero mutation.

    Also, what are your thoughts on DNA fragmentation in males sperm with grade 3 varicocele? I have read if can lead to day 3 decline of embryo? Is it worth fixing. My husband and I have gotten such mixed messages on this.

    Thank you so very much for your time!

    LB

    • Geoffrey Sher says:

      The SCSA (that among other things measures Sperm DNA Fragmentation can be helpful. As for PCOS and your Ovarian hyperstimulation, I did a 2 hour webinar (posted on this site ) a few weeks ago on the very subject. i urge you to find this and watch it.

      Please go to the home page of this blog, http://www.IVFauthority.com . When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
      1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      2. Ovarian Stimulation for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      3. ” Ovarian Hyperstimulation syndrome and prolonged coasting”

      4. “PCOS”

      5.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      6. “IVF success: Factors that influence outcome”

      7. “Use of the Birth Control Pill in IVF”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization, the ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

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