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PGS and Assessment of Egg/Embryo “competency”: How Timing, Process, and Methodology Can Affect Reliability

by Dr. Geoffrey Sher on May 22, 2016

About a decade ago, we, (Sher, and Keskintepe, L; et al) introduced full chromosomal karyotyping for preimplantation genetic sampling – (PGS) to assess egg/embryo “competency” for IVF. We performed and reported on 3 separate studies that served to herald transformation in the field and provided an opportunity to positively impact egg cryostorage for fertility preservation (FP) and donor egg banking.

  1. 2007: Using metaphase comparative genomic hybridization (mCGH) we assessed the chromosomal integrity of 1st polar bodies (PB-1) biopsied from human donor eggs. We then fertilized normal (euploid) eggs with donor sperm and transferred up to two resulting blastocysts to recipients. We reported a viable pregnancy rate of > 50% per embryo transfer  following the transfer of up to 2 advanced embryos (blastocysts). These rates were  significantly higher than national average results for comparable patients, reported by SART for the transfer of non-tested embryos.
  2. 2008: We biopsied single cells (blastomeres) from 5-9 cell day-3, cleaved embryos for mCGH testing and then allowed the embryos to continue in culture to day 5-6 and vitrified those that survived to the blastocyst stage. The transfer of up to two (2) euploid blastocysts in a subsequent cycle (“Staggered IVF”) resulted in a similar viable pregnancy rate per embryo transfer as that which we reported in our first study in 2008:
  3. 2008: Finally, we improved the  IVF birth rate per frozen egg from a reported 4-6% (when no PB-1 karyotyping was done)  to 28%, when only mCGH-normal/euploid frozen eggs were thawed, fertilized and up to two resulting blastocysts were transferred.

This break-through soon spawned rapidly growing interest in PGS with full egg/embryo karyotyping and heralded the onset of an era where this form of embryo selection would become inculcated into the IVF diagnostic armamentarium.

At first, virtually everyone performed PGS full karyotyping on single cells derived from eggs or day-3 cleaved embryos. However, since the performance of mCGH is a labor-and cost-intensive exercise which requires several days to perform, it soon became apparent that the use of this methodology was cost prohibitive. A more cost-effective approach was sought, leading to the replacement of mCGH with array-CGH (aCGH) where the process took only a few hours and the analytics was abbreviated and much easier.

We had been reporting excellent results with mCGH, performed onsite both on PB-1 and on day-3 blastomeres and where the amplification process was conducted onsite, ASAP following performance of the biopsies. So, being firm believers in the adage that “if it ain’t broke, don’t fix it”, we elected to continue using mCGH for PB-1 and day 3 blastomere embryo karyotyping. However, given that performance of mCGH testing, onsite in our own genetics laboratory soon  became cost-prohibitive, we negotiated an exclusive arrangement with a leading genetics center of excellence in Turkey for a   lower fee and  thereupon began outsourcing all  biopsied specimens (derived from eggs and embryos) for amplification, hybridization and analysis.

An initial study using aCGH reported from a large and reputable center in Colorado where lower cost aCGH analysis was used for testing day-3 embryos, produced results and a degree of reliability that was comparable to what we had reported on using mCGH. It resulted in this more cost-effective aCGH process becoming recognized as the PGS “gold standard”. Soon more and more IVF centers began sending day-3 biopsy specimens to remotely located genetics laboratories that sprung up all over. But unfortunately  reported results did not match the favorable results previously reported by us in Las Vegas and from Colorado, leading geneticists to believe that the this discrepancy was likely due to the fact that a single cell (blastomere or PB biopsy) did not generate enough DNA (about 20pg per cell)  to permit reliable CGH analysis and that much more DNA (2-3 times the amount) was required to perform the assay reliably  It was proposed that this would require 4-10 cells and thus that the material would need to be obtained through biopsying the trophectoderm (TE) of  blastocysts..

Soon TE, blastocyst biopsies started to replace day 3 biopsies. However, it soon became apparent that even multicellular TE biopsies failed to significantly enhance reliability of the PGS results reported. IVF outcome statistics simply did not improve across the board. Moreover, the examination of miscarried concepti resulting from the transfer of PGS-tested embryos often showed discordance between result reported through aCGH and those found through other tried and tested standard genetic methods. All this soon led to a growing lack of confidence in the reliability of PGS testing using aCGH performed on TE.

Citing a possible flaw in the aCGH process as being responsible for the discordance, experts began to advocate alternative PGS testing methods such as SNP-array, and next generation gene sequencing –NGS (among others). But even this failed to significantly improve the predictive reliability of PGS testing, continued to cast suspicion on the validity of previous claims made regarding the reliability and value of PGS embryo testing. To make matters worse, recent reports suggest that younger women might not benefit from PGS testing, proposing that such testing be limited to older women, and those with repeated IVF failure or recurrent pregnancy loss.

The fact that we in Nevada had noted a drop off in our own success using mCGH following the outsourcing of all mCGH testing that coincided with our outsourcing of all testing to a laboratory in Europe, alerted us to the possibility that the belief that the deteriorating results with PGS on the basis of the technology being flawed, was probably wrong. Was it possible that differences in performance and reliability could be due to the biopsied DNA specimens becoming corrupted prior to the analytic process? Could it be that embryo DNA biopsies do not travel well and are damaged in transit to a remotely located genetics laboratory? In addition, could the freezing of biopsied DNA in order to prepare them for remote transportation in and of itself have a damaging effect and could a delay in initiating amplification also lead to corruption of the DNA?

Notwithstanding the above, it is a fact that accurate PGS is probably best performed using NGS. The question however, is whether it is preferable to perform the test on a single cell biopsy on CD 3 or is it preferable to biopsy TE derived from a day 5-6 blastocyst. Clearly biopsying a multicellular (>100cells) blastocysts by allowing access to several cells at a time, has the advantage of providing access to much more DNA than when a single cell (blastomere) is extracted from a 5-10 cell day 3 embryo. But does this enhance the reliability of PGS. I know that most would say that it does …but I am unconvinced. Consider the fact most numerical chromosomal aberrations (aneuploidy) involving day- embryos originate during maturational division (meiosis) in the egg and that many such meiotic aneuploid embryos do not survive to the blastocyst stage. This is because all the embryo’s cells are aneuploid. Thus, embryos affected by meiotic aneuploidy are permanently “incompetent”. They cannot recover. In contrast, aneuploidy can also result from replication errors during repeated cell division that follows fertilization (i.e. during mitosis). In such cases some of the embryo’s cells will be aneuploid while others will be normal. This is referred to as “mosaicism”. Mosaicism is potentially reversible (autocorrected) while meiotic aneuploidy is not and there is no known method whereby karyotyping of single cells can differentiate between meiotic and mitotic aneuploidy (mosaicism).

I simply do not buy into the argument that mosaicism is more prevalent in early embryos than in blastocysts. After all, mitotic cell replication is far more advanced in blastocysts than in day 3 embryos. Thus the opportunity is greater for mitotic errors to occur in blastocysts than in a day-3 embryos. Thus in my opinion, the closer to fertilization that the embryo biopsied is performed, the lower the likelihood of encountering mitotically aneuploid cells.

Clearly, unless the above mentioned issues are investigated and resolved soon, the entire concept of PGS embryo selection will likely soon fall into disrepute. That would indeed be a pity because we know that if conducted responsibly and selectively, such testing can have great benefit. We MUST act fast and act NOW to avoid this from happening.

In summary, while I do concur that blastocyst biopsy is a reliable method by which to access DNA material for PGS testing, I strongly suspect that the reliability of PGS embryo karyotyping has less to do with the method of analytics employed (mCGH, aCGH, SNParray, NGS) and more to do with preservation and preparation of the biopsy specimen for analytical processing.

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  • Marlen - October 24, 2016 reply

    #1 In 2014, at age of almost 41, had 27 oocytes retrieved and frozen
    #2 – In January 2016, out of the 27 oocytes, had 4 oocytes fertilized, 2 good quality embryos (not sure of the grading was told good quality) both transferred both – chemical pregnancy
    #2 – In May 2016 – had 16 oocytes fertilized, 2 good embryos (not sure of the grading but again good quality) transferred – BFN
    #3 – In Aug 2016 – Did a mini-cycle egg retrieval for additional oocytes, and yield more (now a total of 16, 9 from mini-cycle and 7 oocytes remaining from 2014 retrival
    #4 – Fertilized all 16, 5 made to blastocysts, and all PGS (1 NORMAL-grade 3B+C+ but euploid). Note that PGS was biopsy on Day 3 and results received for Day 5 fresh transfer of the 1 normal embryo. Transferred 1 embryo 10-24, and found out today, BFN for the 1 euploid embryo.

    Now that I am 43, and no more oocytes in storage, I am trying to decide on my next step. Earlier this year, my AMH level was around 3, and FSH levels always under 13, basically in the range of 5-8. I have been diagnosed with PCOS and taking metformin. Additionally, I had HSG, and other tests conducted, all are fine. I do have fibroids but 4 doctors have informed me that my fibroids are not in a position that it will impact implantation or pregnancy. I am healthy 28 day regular cycles, normal flow despite the fibroids. I am not sure what to do next. I was able to get a normal embryo, and my levels are still good at the age 43 (just turned 43). Should I try IVF again?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 24, 2016 reply

    Older women as well as those who (regardless of age) have diminished ovarian reserve (DOR) tend to produce fewer and less “competent” eggs, the main reason for reduced IVF success in such cases. The compromised outcome is largely due to the fact that such women tend to have increased LH biological activity which often results in excessive LH-induced ovarian testosterone production which in turn can have a deleterious effect on egg/embryo “competency”.
    Certain ovarian stimulation regimes either promote excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), augment LH/hCG delivered through additional administration (e.g. high dosage menotropins such as Menopur), or fail to protect against body’s own/self-produced LH (e.g. late antagonist protocols where drugs such as Ganirelix/Cetrotide/Orgalutron that are first administered 6-7 days after ovarian stimulation has commenced).

    I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of a long pituitary down-regulation protocol coming off a birth control pill, augmented by adding supplementary human growth hormone (HGH). I further recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing/NGS)-normal blastocysts in such cases. This type of approach will in my opinion, optimize the chance of a viable pregnancy per embryo transfer procedure and provide an opportunity to capitalize on whatever residual ovarian reserve and egg quality still exists, allowing the chance to “make hay while the sun still shines”.

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • Implications of “Empty Follicle Syndrome and “Premature Luteinization”
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
    . Uterine fibroids
    . Polycystic Ovarian Syndrome (PCOS

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
    Geoff Sher

  • Katy - May 31, 2016 reply

    *typo – 6 hatching blastocysts at day 5, not 6 expanding blasts

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 1, 2016 reply

    Copy!

    Geoff Sher

  • Katy - May 31, 2016 reply

    Thank you for such a helpful and interesting POV about the merits of PGS testing approaches. I am currently having PGS testing done and realise that my situation probably goes against everything you have generally recommended for PGS, however I do have one question I would be grateful for your thoughts on

    I am 34 with good ovarian reserve, therefore based on what I have read, I’m guessing you may say I am a poor candidate for PGS as a reasonable number of my embryos should be euploid?

    We decided to opt for PGS after miscarrying an embryo that cytogenetic analysis showed to be euploid – ie it was due to the soil and not the seed. We’re taking a multipronged approach to optimising the uterine environment for a subsequent transfer, however we therefore wanted to do PGS as much of a diagnostic exercise as anything – as if we transferred one of the untested frozen blastocysts, and the cycle failed or I miscarried again, we wouldn’t know it was due to the seed or the soil.

    We have a large number of embryos, and so trying to pick a good one at random felt like lucky dip (or Russian Roulette!), and could potentially lead to consecutive failed FET. Or at the other end of the spectrum, if we transferred two blasts, the risk of twins could also be unacceptably high.

    Hence we’ve decided to do PGS. My lab has had considerable experience conducting PGS on already frozen embryos, and their data shows that euploid embryos almost always survive the freeze / thaw process – those that don’t are almost always aneuploid. Thus as our 4 frozen embryos are blasts, we have no choice but to biopsy these at blastocyst stage!

    We did another fresh cycle, and had 19 good quality embryos at day 3. To biopsy and test all 19 embryos would be prohibitively expensive (at £3000 for 8 embryos, with each additional embryo tested @ £300) – however by day 5 we have 6 expanding blastocysts, and another 5 early blasts the lab are watching to see if they reach the required stage for biopsy and freezing tomorrow (day 6).

    Given that, as you have said many times on your blog that embryos that don’t make it past day 3 would almost certainly be aneuploid, I would have thought that by opting for blastocyst biopsy we’ve already weeded out a number of incompetent embryos before testing?

    I’d be really interested to hear your take on this scenario, and if you think day 3 biopsy would have been preferable? The PGS will be performed using NGS.

    Thank you for publishing so much useful information on PGS and embryo selection – it has been incredibly informative and interesting. Would be very interested to hear your POV on day 3 vs day 5 biopsy with such a large number of embryos! Thanks in advance

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 1, 2016 reply

    In my opinion, thawing cleaved (day 2-3) embryos and then allowing them to go to blastocyst before biopsying them is in my opinion a relatively sound, rational and safe option. The problem arises when blastocysts are thawed, biopsied and then immediately transferred. This is harmful to the blastocysts and the pregnancy rate (although not zero), is much reduced. This having been said, I still believe that at your young age where 1:2 eggs and therefore, blastocysts are likely to be euploid, there is no benefit in doing PGS. Simply transfer 2 blastocysts. Ifone is euploid it will gace a 60% chance of propagating a viable pregnancy.

    In your case however, since a PGS-normal embryo did not take, there is a strong possibility of an anatomical or immunologic implantation dysfunction. I strongly advise that this be assessed before you undergo any further ET’s whether the embryos to be transferred aretested or not.

    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly

    .
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF

    I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

    Email: Julied@sherivf.com

    OR

    Phone: 702-533-2691
    800-780-7437

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Good luck!

    Geoff Sher

    Katy - June 1, 2016 reply

    Thank you Dr Sher – I am very grateful for such a helpful and thoughtful response

    The frozen embryos were frozen as early blastocysts, rather than cleaved embryos, therefore could only be biopsied as blasts.

    The question was more around our fresh embryos – with 19 cleaved embryos at day 3, if you recommend day 3 biopsy over day 5, would not culturing the embryos to blastocyst therefore weed out a large number of aneuploid embryos before PGS testing took place?

    I appreciate the rationale for a 1:2 ratio of euploid embryos, however does that not also make the risk of twins with double blast transfer significantly higher? If I had wanted to transfer two blasts my clinic would have happily done so, as it’s our prerogative as paying patients,but we would have had to sign a waiver saying that we understood the risks of twins were very high at my age, and were doing so agains medical advice.

    I have been investigated for immunological implantation dysfunction and apart from very very mildly elevated NK Cells in the NK cytotoxicity assay, there were no major immunological red flags. We are however going to be treating with prednisolone, intralipids and clexane in an upcoming FET, to cover off even any mild immunological issues.

    We think the most likely cause of the miscarriage was due to lining which only thickened up AFTER the trigger: it was 5.5mm at EC, and then 8.5mm at day 4, when we elected to go ahead with transfer – however this was already under the influence of progesterone, and therefore the lining was likely suboptimal

    Two months of estradiol tablets while I was pregnant seem to have upregulated the oestrogen receptors in my endometrium, and this fresh (banking cycle), my lining grew to 11.1mm before trigger, therefore we are hopeful that I will respond to oestrogen in an upcoming FET and that my lining will thicken up appropriately

    Unfortunately in the UK we are unable to obtain your magical vaginal viagra pessaries, as we don’t have compounding pharmacies who are able to manufacture the necessary formulation, and as far as I understand from other clinics (please do correct me if I am wrong), the compounding pharmacy you recommend would not fill prescriptions issued from overseas. I would be only too keen to add in vaginal viagra to the mix for my FET, the issue is being able to obtain the effective formulation!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 1, 2016 reply

    In my opinion, it would be safe to either biopsy the embryos in the cleaved stage of development, allow them to go to blastocyst and then vitribanking them while awaiting the PGS result…OR, taking them to blastocyst, biopsying them at this stage and refreezing them while awaiting the PGS results.

    There is no problem in doing single blastocyst transfers…The cumulative transfer of one at a time would yield the same overal chance o fa baby without a great risk of twins, only it would require up to 2 attempts to achieve this chance.

    Indeed, using a double euploid blastocyst transfer the twinning rate would likely be about 40% while with 2 untested blastocysts it would probably be about 25%. But given that about 1: 2 untested blastocysts would likely be chromosomally “incompetent” (aneuploid) and thus not likely to propagate a viable pregnancy, it would require up tto 2 transfers (one embryo at a time) to achieve the same chance of a baby as when 2 euploid (potentially competent) embryos were transferred with a single procedure.

    The fact that the thickness of your endometrial lining went up to 11mm means that under optimal circumstances an adequate development is possible and that something else (perhaps the protocol used for stimulation before, rather than a poor endometrium was responsible for the original poor response. Frankly, if that is the case, the use of vaginal Viagra would probably not have helped anyway.

    Good luck and please keep me updated on your progress!

    Geoff Sher
    702-892-9696

    Katy - June 2, 2016

    Thank you Dr Sher!

    We are very pleased that the final tally is 12 blasts now biopsied for PGS and frozen – 9 from this fresh cycle, plus 3 frozen blasts thawed, biopsied and refrozen. Now to await the results!

    My lining issues had been – until my pregnancy – persistent in both my natural and stimulated cycles. In my natural cycles my lining never got above 4.5mm. In my first IVF cycle my lining didn’t get above 7mm, in my 2nd it only thickened up once we added in oestradiol tablets.

    The stims protocol was identical for all 3 cycles – short antagonist with Gonal-F and Cetrotide.

    My Dr theorised that my lining may well have become atrophic after long term use of the pill, and the oestrogen receptors in my endometrium had become non responsive. He hoped that cumulative exposure to oestrogen would upregulate the receptors and ’teach’ my lining to respond to my body’s natural oestrogen.

    Perhaps then the 2 months of oestrogen tablets throughout my pregnancy did something – so that this time around, my third cycle, my endometrium responded and thickened up appropriately?

    Hysteroscopic evaluation of the uterine cavity showed normal uterine anatomy and no evidence of any adhesions post D&C. I am hopeful, therefore, that my lining will be similarly responsive in our upcoming FET – and that the inability to access your magical vaginal viagra pessaries in the UK will become a moot point!

    Many thanks once again and very best regards

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 2, 2016

    Goodluck!

    Geoff Sher

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - June 1, 2016 reply

    In my opinion, it would be safe to either biopsy the embryos in the cleaved stage of development, allow them to go to blastocyst and then vitrifying and banking them while awaiting the PGS result…OR, taking them to blastocyst, biopsying them at this stage and refreezing them while awaiting the PGS results.

    There is no problem in doing single blastocyst transfers…The cumulative transfer of one at a time would yield the same overall chance o fa baby without a great risk of twins, only it would require up to 2 attempts to achieve this chance.

    Indeed, using a double euploid blastocyst transfer the twinning rate would likely be about 40% while with 2 untested blastocysts it would probably be about 25%. But given that about 1: 2 untested blastocysts would likely be chromosomally “incompetent” (aneuploid) and thus not likely to propagate a viable pregnancy, it would require up to 2 transfers (one embryo at a time) to achieve the same chance of a baby as when 2 euploid (potentially competent) embryos were transferred with a single procedure.

    The fact that your lining thickness went up to 11mm means that under optimal circumstances an adequate development is possible and that something else (perhaps the protocol used for stimulation before, rather than a poor endometrium was responsible for the original poor response. Frankly, if that is the case, the use of vaginal viagra would probably not have helped anyway.

    Good luck and please keep me updated on your progress!

    Geoff Sher
    702-892-9696

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