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.

140 Comments

  • Lynsey says:

    I am 35, I don’t have Pcos but my consultant says I act like someone who does. I am overweight. 5years ago we had ivf with menopur and cetrotide. We had 14 eggs but only 3 were mature enough to fertilise but 1 made it to be our perfect little boy. We are trying for baby number 2. On our last IVF cycle we had ICSI with the same drugs as last time. I started on 2 vials of menopur and by day 6 my eggs were tiny so they upped it to 3vials and I continued for 16 days total before HCG trigger. They collected 15 eggs but all were GV apart from one, that one did fertilise but only lasted 1 day. Wet are starting the next cycle and they have put me on DHEA and will change to Gonal f but everything else they are going to do the same and this worries me. Can you offer any advice please. How can I help my eggs mature. Many thanks

    • Geoffrey Sher says:

      Hi Lynsey, I would need much more information to comment authoritatively. What I can say is that it likely has to do with the protocol used for ovarian stimulation needing revision. I can tell you that I do not advocate the use of DHEA. While it probably does no harm in women who have normal ovarian reserve, it in my opinion is nnot beneficial. And when it comes top lder women and those with DOR, the fact that it is converted to testosterone in the ovaries and ibn such women, too much ovarian testosterone can have a damaging effect on egg development, I do not prescribe it.

      Please go to the home page of 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. “Nutritional Supplements 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.

      Important Announcement:

      Dr Al Peters (Medical Director at SIRM-New Jersey), and I ,recently established the “SIRM Reproductive Immunology Forum(SRIF) which will provide a venue where you can address and hopefully find solutions to problems relating to Immunologic Implantation dysfunction (IID) that often manifest with “Unexplained” infertility, IVF Failure and Recurrent Pregnancy Loss (RPL..

      To this end we established http://www.InfertilityImmunology.com , a dedicated website where you can:
      • Register with SIRF
      • Request and receive (free of charge) a PDF copy of our book: “Unexplained” Infertility and Miscarriage : The Immunologic Link”
      • Be kept abreast of what is current in the IID arena
      • Post questions for Dr Peters and I to respond to and,
      • Interact with other patients on a separate discussion board dedicated to this.

      We look forward to hearing from you!

  • Beth says:

    Hello – I’m currently 32. I’ve had pcos my whole life. I was overweight and only had 2-3 periods a year. I lost 70 lbs and started having regular 28-30 day periods before I had ivf in Jan. I don’t remember what the numbers were, but my doc said she looked at two factors for pcos in my blood work, one was normal and the other was a bit high. I think the “normal” one was my AMRH, but I’m not positive, sorry. I don’t remember the other one.

    We also have MFI. He had varicocele surgery in Dec.

    Stims were 150 follistim and 75 menopur with ganirelix on day 6 and hcg trigger on day 11.

    We retrieved 24 eggs, 18 mature, 16 fertalized. On day 3 there were 13 embryos that all looked pretty good. On day 5 there was only one 5AB and one 4BB blast. There were 4 others that weren’t good and apparently weren’t salvageable on day 6. We transferred the 5AB blast and froze the 4BB. The transfer ended in a chemical pregnancy.

    It was assumed that my husband’s sperm was the problem, likely due to DFI, however we had it tested 2 months later and it came back at only 7% DFI. I doubt his sperm could have improved that dramatically, even with the surgery, that soon. I’m starting to think the protocol was the problem. Thoughts?

    I appreciate your time and thank you in advance for any suggestions you have.

    • Geoffrey Sher says:

      Hi Beth,

      I tend to agree with you that this could be a protocol issue. Women who have PCOS do tend to have poorer quality eggs but they also produce a large number at a time. In fact PCOS women are often at risk of developing ovarian hyperstimulation syndrome (OHSS) which is a serious complication. Often times, the fear of OHSS developing will lead doctors to trigger earlier than ideal with hCG, use a lower dosage or even trigger with Lupron. In my opinion while such tactics might prevent serious OHSS-related complications, it also results in poorer quality eggs and embryos.

      My approach in cases such as yours is consistently to use a long pituitary DR protocol with an agonist, coming off 1-2 months on the BCP. The latter is intended to lower LH and thereby reduce stromal activation (hyperthecosis) in the hope of controlling ovarian androgen release. I then stimulate with low dosage FSHr to which I add a smidgeon of LH/hCG (Luveris/Menopur) from the 3rd day and watch for the # of follicles and [E2] starting on the 7th day of COS. If there are > 25 follicles, I keep stimulating (regardless of the [E2] until 50% of all follicles reach 14mm. Then, provided the [E2] is >2500pg/ml, I stop the agonist and the gonadotropin stimulation and follow the E2 (only) daily, without doing further US examinations. The [E2] will almost invariably climb and I watch it go up (regardless of how high the concentration of E2reaches) and track it coming down again. As soon as the [E2] drops below 2500pg/ml (and not before then ever), I administer 10,000U hCGu or hCGf (Ovidrel/Ovitrel-500mcg) as the “trigger” and perform an egg retrieval 36h later. ICSI is a MUST because “coasted” eggs usually have no cumulus oophoris and eggs without a cumulus will not readily fertilize on their own. All fertilized eggs are cultured to blastocyst (up to 6 days). And up to two (2) are transferred transvaginally under US guidance.

      The success of this approach depends on precise timing of the initiation and conclusion of “prolonged coasting”. If you start too early, follicle growth will stop and the cycle will be lost. If you start too late, you will encounter too many post-mature/cystic follicles (>22mm) that usually harbor abnormally developed eggs.

      Use of the above approach avoids unnecessary cycle cancellation, severe OHSS, and optimizes egg/embryo quality. The worst you will encounter is mild to moderate OHSS and this too is uncommon.

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

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

      6. “IVF success: Factors that influence outcome”

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

      8. “OHSS”

      9. “PCOS”

      Consider calling 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.

      • Beth says:

        Hi Dr Sher- I just went through a second round of IVF. We changed the protocol to long lupron with 1/2 dose of menopur. I ended up with 25 eggs oh which 21 were mature and and they all fertilized. By day three 16 were still viable. We ended up with 7 embryos on day 5 and they were all sent for PGS testing. I just got the news that ALL 7 were abnormal. My doc says they’ve never seen this before in someone my age (32) and even though I have PCOS, they think it’s due to my husband’s sperm and they’re recommending donor sperm. I don’t understand how that could be given that his dfi was only 7%, but they feel strongly that my eggs responded appropriately. I’m just wondering if you have any additional insight or if you’ve ever seen something like this happen and have any recommendations

        • Geoffrey Sher says:

          How did you get triggered. In my opinion, this is more likely to happen when 250mcg of hCGr( Ovidrel) is used for the trigger. Ideally the dosage should be 500mcg or 10,000U of hCGu (Pregnyl/Novarel/Profasi). I also think this is more likely when a Lupron trigger is used.

          Geoff Sher

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