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    • IVF Case Study # 8: An Older Woman With Recurrent IVF Failure, Diminished Ovarian Reserve and Immunologic Implantation Dysfunction

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      This continues our series of IVF case studies. Here in our 8th case we discuss a couple who had experienced 22 previously unexplained IVF failures who had diminished ovarian reserve (DOR) plus immunologic implantation dysfunction (IID) and subsequently conceived when treated with an agonist/antagonist conversion protocolwith estrogen priming and selective immunotherapy to down-regulate activated natural killer cells (NKa).

      Background
      Christine, a 42 year old physician from Australia had endured 23 prior unsuccessful fresh embryo transfers over a period of more than a decade. By the time I got to know her she had severelydiminished ovarian reserve (her day-3 FSH was 26MIU/ml).

      Follow-Up
      After a lengthy telephone consultation with her, I urged her to send a blood sample from Melbourne, Australia to a reputable Reproductive Immunology Reference Laboratory in Southern California for testing to screen for immunologic implantation dysfunction (IID). It soon became apparent that she had an autoimmune thyroid condition (antithyroglobulin and antimicrosomal antibodies) along with activation of uterine Natural Killer Cells (NKa+). After controlled ovarian stimulation(COS) using an aggressive agonist/antagonist conversion protocol with estrogen priming, and pre-treating her immunologic implantation dysfunction (IID) with selective immunotherapy, I harvested just three eggs. We subsequently transferred two embryos to her uterus. She conceived in this cycle and gave birth to a healthy baby boy nine months later.

      Commentary
      This case shows that there is no merit in doing IVF over and over again in the face of repeated prior failures, without making a strong effort to determine the reason for such failures. In Christine’s case, by the time I saw her for the first time, she already had severely diminished ovarian reserve (DOR) as well as an immunologic implantation dysfunction (IID) linked to Natural Killer cell activation (NKa). We addressed the severe DOR by stimulating her with an agonist/antagonist conversion protocol plus estrogen priming and harvested 3 mature eggs (MII’s) and transferred 2 good quality embryos. We addressed the IID through selective immunotherapy by down-regulated her NK cell activity and corticosteroid therapy to establish a favorable uterine environment. She duly conceived.

      This case also demonstrates that in women with severe DOR, diminished egg/embryo quality can in part be effectively by using an individualized approach to ovarian stimulation such as the agonist-antagonist conversion protocol with estrogen priming; LA10-E2V.

      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.

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      18 Responses to “IVF Case Study # 8: An Older Woman With Recurrent IVF Failure, Diminished Ovarian Reserve and Immunologic Implantation Dysfunction”

      1. April Jones says:

        Hi Dr Sher

        Reading this case study has prompted me to seek your advise. I am a 41 years old and my husband and I have been trying to conceive since we married (I was aged 37 at the time). After a year of no success we sought fertility advice. Investigations indicated no problems with my husband, however I had a low ovarian reserve (high FSH with only a 21 menstrual cycle) and ASA at 70% levels. We were told we had a 1% chance of pregnancy. We quickly opted to IVF/ICSI with stimulation to achieve 6 eggs collected, 2 survived to Day 3. We had a FET with one (the max allowed at the time) without success, 3 months later we used the other embryo in a frozen cycle, again no success. After moving overseas (nearly 2 years later) new tests show I have low ovarian reserve (FSH of 20) however LH and E2 levels are apparently normal, my antral follicle count is “lowish” but I am still ovulating according to the most recent ultrasound and my cycle length is now 25-26 days for some reason. We are currently in the 2WW afer having a brief aggressive stimulation cycle using only Gonal F (9 days) which reaped only 2 eggs (one of which made it to 3 days and was transferred). Medication-wise I am taking: Progesterone and estrogen support, Heparin, and Prednisolone and Aspirin as well as some dietary supplements. My question is, is there anything else you can suggest which might be added or changed to our protocol to improve our chances – particularly given the ASA seems to be something which will prevent a natural conception no matter how many viable eggs I have left. Anything you can offer in the way of advice would be so appreciated!

        • Geoffrey Sher says:

          The ASA issue mandates ICSI of course.For input on ovarian stimulation in older women and those with DOR, might I recommend that you go to the home page on this site, find a “search bar” in the upper right hand column and type in the following subjects into the bar and it will take you to all the relevant articles I posted there. Also read up on “embryo banking with staggered IVF.

           “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
           “Agonist/Antagonist Conversion Protocol”
           “IVF success: Factors that influence outcome”
           “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
           “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
           “Staggered IVF”
           “Gestational Surrogacy with St-IVF”
           “Egg Donation”
           “Egg Donation with St-IVF
           “Embryo Banking”

          Also, you might consider calling 702-699-7437 to set up a video conference with me so we might discuss your case in detail.

          Geoff Sher

      2. Rama says:

        On 28th December 2012, I had an ultrasound to check my ovaries. I had 2 antrial follicles on left ovary and 3 antrial follicles on right ovary. Is this very low antrial follicle count. I am thinking to use DHEA 10 mg thrice a day. I am on Metformin. Can I take DHEA with Metformin. I am using Metformin since 2 years. Now I am not insuin resistance and my insulin levels fasting are 10.3 mu/L. my DHEAS levels are 4.5umol/L. testosterone 0.6nmol/L. oestradiol 66pmol/L on day 2 of my cycle.My age is 41.8 years. My question is can i take both metformin and DHEA to improve my egg. Here in australia DHEA is not used it is banned.

        • Geoffrey Sher says:

          This is a low AFC. I would be interested in learning what your day 3 FSH was and what your AMH is. I would not use DHEA as it metabolizes to testosterone in the ovary and too much testosterone in a woman with potentially diminished ovarian reserve (DOR) can compromise egg/embryo development.

          Happy new year,

          Geoff Sher

      3. Julia says:

        Dear Dr Sher,

        I am 43yrs old next month and running out of time.

        In September 2012, FSH was 6.5iu/L (Day 2) and AMH was <1.1. DHEA also 1.1 umol/L in Dec 2012. I had 2 failed IUI’s Oct & Nov 2012 (Nov cycle – 10mg pred and Clex40mg).

        In Dec 2012 a laparoscopy showed mod to severe endometriosis.

        Two Biopsies revealed raised/high uterine CD57 NK cells: Dec 2012: 20/mm2 during late secretory phase and in Feb 2013: 30/mm2 during proliferative phase. Blood NK cells seem normal except a separate surface marker blood test revealed B cells CD19 at 11% in Dec 2012.

        My first IVF attempt failed in Jan 2013. This was after aggressive FSH stimulation (900iu for 15 days, 600iu for 2 days), prednisone (raised to 20mg post egg collection) and clexane 20mg produced only 1 egg from 4 follicles.

        I am waiting for my period in the next few days to begin a new IVF cycle and considering suggesting to my very supportive Fertility specialist Intralipid 20% (1 week prior to implantation) and clexane, but this time dropping the prednisone as I am negative to ANA, Anti-DNA (FEIA), Beta 2 GP IgG, Cardiolipin IgG & IgM and histone autoantibodies. Thyroid levels (including antibodies) were normal.

        Do you have any suggestions, as your advice may very well be life changing. Many thanks.

        • Geoffrey Sher says:

          In my opinion, before it is too late, you should consider Embryo Banking with Staggered IVF and CGH embryo selection. I can help here. The immune issues can also be addressed.

          Please go to the home page of this blog, (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 in IVF: Why is it important to down-regulate LH?”

          3. “Agonist/Antagonist Conversion Protocol”

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

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

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

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

          8. “IVF success: Factors that influence outcome”

          9. “Staggered IVF”

          10.“Embryo Banking”

          11. “Egg Donation”

          Please consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.

          Geoff Sher

      4. Julia says:

        Hi again, I forgot to mention for the IVF cycle the 1 egg fertilised and the day 5 embryo (morula) was transferred.

      5. Julia says:

        Also Lupus not detected, Protein C, Protein S FAg, AT III, PT and APTT all normal.

      6. Julia says:

        Thank you so much for your reply Dr Sher. I live in Australia. Do you provide consults to international patients (after bloods required are done) and advise protocols to the patients’ fertility specialist without the patient having to come to the USA?

        • Geoffrey Sher says:

          It is not right to (and I would not) recommend treatment to someone under another physician’s care. However. if contact by an outside physician, I am always willing to give my input….and I often do via phone.

          Good luck!

          Geoff Sher

      7. Julia says:

        Ok thanks Dr Sher – I will call your clinic to check what has to be arranged for my fertility physican to call you. Thanks so much. Julia

      8. rama says:

        recently i had biopsy of my endometrium and my doctor told that i am having uterine nk cells 70, which is very very high count. he also said that in his service he have seen only 20 nk cells. which is high, but in my case it is very very high which is 70 cells and he gave me prednisolone 25 mg. i am trying to concieve since 3 years. my age is 42. i am on metformin 1000 mg, and i had a 6 week miscarriage in 2011 october. and one failed ivf with only 3 eggs retrived. my AMH is 0.5 ng/ml on december 2012. I am ovulating every month. Can i concieve with uterine NK cells 70 at my age 42

        • Geoffrey Sher says:

          Respectfully, the test you need is the NK cell activity test (K-562 target cell test). For this I suggest you contact Reprosource in Boston, MA. Also, steroids will not reduce this activity. You would need Intralipid. See below.

          Please go to the home page of this blog, (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. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.

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

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

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

          Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.

          Geoff Sher

      9. lucy says:

        Hi Dr. Sher,

        I’m 36 with DOR (FSH=13, AMH=0.53)never pregnant since several years of trying.

        My question is if an elevation of NK at 13% requires treatment during IVF, cortisone? intra-lipids? I have negative ANA, IgG and IgM.

        I also have MTHFR and PAI1, do I need enoxaparine? clexane or lovenox? baby aspirin? I have negative for lupus antocoag, normal Prot C, Prot S, ATIII, APCR and Factor VIII. No mutation Factor V Laiden and Prothrombin Genotype.

        I have been taking DHEA (50mg AM and 25mg PM) along with CoQ10 (400mg AM and 200 PM)and Inositol (500mg three times a day) I was told this may improve EGG QUALITY, is this so? I read you said DHEA sometimes is not advised.

        I thank you in advance with all my heart for your comments!

        • Geoffrey Sher says:

          I do not recommend DHEA in women with DOR. With DOR, a very strategic protocol of stimulation is advised (see #s 1-3 below)

          AS for the rest…I would need much more detail to comment adequately, especially on the NK cell “activation”.

          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 corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.

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

          2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”

          3. “Agonist/Antagonist Conversion Protocol”

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

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

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

          7.“A personalized, stepwise approach to IVF

          Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail

          Geoff Sher

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