Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Dear Dr. Sher:
I am writing to inquire about IID in regard to the problems me and my wife have conceiving. We suspect we have a problem with implantation, and after reading your blog I would like to know a bit more details about the immunological tests that we need to do. She has a tested for NK cell concentration twice, and it was 6% in a normal range 5.6 to 31%, and 2% in a range of <12%. You say that it is the activity of these cells that matters, not the concentration. So, shall we test the activity against K-562 cells no matter how low the NK cell concentration is? Also, we found she has elevated concentration of T-suppressor cells CD3+CD8+, measured at 45% and 47% relative to a reference range of 11-38%. Do we need to test the activity of these as well, and if so, how is this done? She also has elevated NKT cells CD3+CD56+ at 15% for a range of 2-11%. Do we need to test the activity of these? In general, I could not understand how is the activity of CTL cells measured. We also need to know what APA test to do. We have done some only on concentrations and they were in the norm. Do we need to focus on some very specific APA's, though?
I also wonder if it matters whether blood samples are used or a biopsy of the uterus is done? Could the levels of these cells be different in the uterus than in the blood? Do we need to test for Th-1 and Th-2 cytokines in the uterus, and in general, do we need a biopsy of the uterus and what shall we ask to be tested there. If we come to the point of doing an IVIg or IL infusion, is it always done in the blood or could we benefit from uterine infusion of some kind?
Finally, my wife is currently in Europe. You say that very few clinics in the world can perform these tests accurately, are there any in Europe that you would recommend, or do we need to do them in the US? I was hoping that we can do at least some of these tests in Europe.
Thank you very much in advance and I would greatly appreciate the opportunity to talk to you.
Best regards,
Stefan
The concentration of NK cells is irrelevant. Your wife should be tested for NK cell activity by the K-562 target cell test and if possible also do an endometrial biopsy for TH-1: TH-2 cytokines. The other parameters need not be explored further. If she tests NKa + by the K-562 test, then the two of you should be tested for an alloimmune implantation issue which means that your DQ alpha and HLA Geotype and hers needs to be matched.
Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented.
Who Should Undergo IID testing?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
•A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy)
•A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
•“Unexplained” infertility
•Recurrent pregnancy loss (RPL)
•A history of having miscarried a conceptus that, upon testing of products of conception, was found to have a normal numerical chromosomal configuration (euploid).
•Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
oFor Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
oFor Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of Intralipid (IL) /immunoglobulin-G IVIG) can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later. In addition, to be effective, IL/IVIG therapy needs to be combined with steroid (dexamethasone/prednisone/prednisolone) therapy to down-regulates (often) concomitantly activated T-cells.
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.
•The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
•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
•Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
•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)
•Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .
*FYI
The 4th edition of my newest book ,”In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Geoffrey Sher MD
Hello Dr. Sher, I was hoping you would have some advice on my situation. I have been diagnosed with unexplained IF. Have had 5 failed IUIs and 4 failed embryo transfers (1 being PGS tested). These all were from the same retrieval. My 2nd retrieval didn’t go very well because my trigger shot failed. But it did result in one AA expanded blast which was PGS normal. In the meantime we also did the ERA test and it showed that I need one extra day of PIO before transfer. So we did that and transferred on 9/26. This transfer took and with very high beta numbers. 1894 at 13dpt and 4653 at 15dpt. Everything was looking good until our first ultrasound at 6w5d. There was nothing but an empty sac. We are devasted and sick of being told that the only explanation for everything we have been through is bad luck. What could be missing? Any thoughts, ideas, or advice would be appreciated. In all the research I have done, I have yet to come across such high beta numbers resulting in an empty sac. I’m just so confused and trying to understand why this happened with a genetically normal embryo. Also I failed to mention that I am 38 years old. Thank you for any suggestions you may have.
Sorry I should have clarified that ICSI was used for fertilization in each case.
Dear Dr. Sher
Thank you for all of your wonderful information and super videos.
My question is on progesterone levels, uterine receptivity and donor egg transfers.
Is there an optimum level of progesterone and dosage/type to take before donor egg blastocyst transfer?
Are cyclogest pessaries/crinone gel good enough or should gestone or PIO injections be administered and how much (each one tends to be 50mg).
Can there ever be too much progesterone and can this harm implantation?
Is there a difference between Fresh and Frozen transfers and the use of progesterone to prepare the uterus.
Your answer would be most appreciated. Cannot find an article here but may have missed it.
Thank You
It is my preference to use PIO rather than vaginal progesterone. Second choice is Crinone 8%, introduced twice daily.
Geoff Sher
Dear Dr Sher,
First of all, thank you for answering these random questions, it is very helpful for us IVF patients and much appreciated. I would really value your insight into my specific problem. I am very confused and sad right now and would really appreciate an outside expert ear.
My first experience of IVF was when I was 36 in 2011 and froze my eggs as I was single at the time. 16 eggs were retrieved, with 14 mature and frozen. The eggs were frozen with the then newish rapid vitrification method – this was around the time egg freezing was declared as being no longer just experimental and social freezing actively promoted.
I went back later at the age of 41 to do a fresh cycle and was extremely fortunate and blessed to have a successful IVF pregnancy immediately. My AMH at the time was 46 (I don’t know in what measure that is- made equivalent to 6 in the US/Europe?) – so very high but no signs of PCOS. 20 eggs were retrieved, 15 fertilised, with 3 day 5 embryos. We used my husband’s frozen sperm as he was overseas at the time. One embryo was transferred and two frozen. I hyper stimulated after transfer, spending 7 days in hospital. I’m not sure, but I think that cycle I was on 225 of gonal f with a pregnyl trigger.
I went back at 42 hoping for a sibling. Neither of the two frozen embryos resulted in pregnancy. Then we decided to do another fresh cycle, at the same time thawing and fertilizing the eggs I froze when I was 36. By this time my AMH had dropped markedly to 14. Still not too bad for my age, but no where near where it was. This time I was on 275 gonal f initially, which was then upped to 450 after three days, as well as orgalutran and with an ovidrel trigger. 10 follicles were seen on ultrasound and 8 eggs retrieved.
I was shocked and devastated to learn the next day that only 2 of my frozen eggs fertilised as well as only 2 of my fresh eggs. We once again had used sperm that was frozen at the same time as my successful fresh cycle the year before as my husband was again overseas. Two embryos were transferred on day 3. The lab tried to get the other two to blastocyst to freeze but they didn’t make it.
The part that confuses me so much is the dismal fertilization rate. What could have caused this? The sperm is from the same batch we had used without problem previously, plus my husband has been tested and has excellent results on his sperm parameters. Could it be my eggs? But why would this apply to two separate very different sets of eggs, especially when I have had good fertilisation rates just over one year ago? Or could this be a problem in the lab or with one or more of the protocols? My clinic says they are very surprised by and are looking into my case, but in the meantime I would really appreciate the advice of someone expert and independent so I know what questions to ask. I would also really like your opinion as to whether at my age (almost 43) with no frozen eggs or embryos there is now any point proceeding with another cycle or any realistic hope for a sibling for my child? We have categorically ruled out using donor eggs.
Oh, I forgot to add that the only reason for my infertility that has been found is one missing tube owing to an unsuccessfully removed fibroid a few years ago (I had a laparoscopy and there is no hydrosalpinx or whatever it is properly called.) I also have only very marginally raised natural killer cells however decided in consultation with my dr. not to treat those.
Thank you for listening!
The likely explanation is a combination of advancing age (with its effect on egg quality/competency/chromosomal integrity) and the protocol used for ovarian stimulation. One thing that absolutely stands out to me is the use of 250mcg hCGr (Ovidrel). In my opinion this dosage is too low. You need 500mcg Ovidrel or 10,000U hCGu (Pregnyl/Profasi/Novarel). If the dosage is too low, it adversely affects meiosis (egg maturation) and increases the likelihood of egg aneuploidy. This alone (in my opinion) could explain poor fertilization. There is absolutely nothing that can be done to slow down or reverse the “biological clock” but there is a great deal that can be done to individualize and optimize the protocol used for ovarian stimulation and thereupon to identify chromosomally normal blastocysts for selective transfer to the uterus.
In my opinion, the protocol used for ovarian stimulation, against the backdrop of age, and ovarian reserve are the drivers of egg quality and egg quality is the most important factor affecting embryo “competency”.
Older women 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 modified, long pituitary down-regulation protocol (the agonist/antagonist conversion protocol-A/ACP) augmented by adding supplementary human growth hormone (HGH) and ultimately, trigger egg maturation with 10,000U hCGu or 500mcg hCGr (see below). 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.
•The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
•Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
•Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
•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
•“Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
•Implications of “Empty Follicle Syndrome and “Premature Luteinization”
•Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .
*FYI
The 4th edition of my book,”In Vitro Fertilization, the ART of Making Babies” is now available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Geoffrey Sher MD