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.
How does IVIG work to suppress immune issues with fertility? Isn’t IVIG given to patients with stem cell transplants etc to boost their immune response? How does it work with IVF to suppress immune response if it’s giving you donor immune stuff? Like how does it actually work? What’s the mechanism?
There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL). Although there are many factors that contribute to such implantation dysfunction, in the final analysis it is activated, “functional” uterine natural killer cells (NKa) in association with cytotoxic-T cells (CTL), which, through the production of cytotoxic cytokines (see below), damage the “root system” (trophoblast) of the embryo, causing the pregnancy either to be immediately rejected or so compromising placentation that early pregnancy loss occurs. Both immunoglobulin-G (IVIG) and intralipid (IL) therapy given in combination with corticosteroids (e.g. dexamethasone, prednisone, and prednisolone) are used to effectively reduce/down-regulate activated NK cells.
NK cells reach the uterus from the woman’s bone marrow, early in the menstrual cycle, as so called “parental” or “progenitor” cells. There, these early NK cells proliferate under the effect of estrogen. Only upon being exposed to progesterone do they begin to propagate “functional” NK cells that release cytokines and promote implantation. The concentration of functional NK cells in the endometrium is maximal about 7 days after exposure to natural(endogenous), or synthetic (exogenous) progesterone ….i.e. corresponding to the time the time when the embryo implants into the uterine lining (endometrium).
Functional uterine natural killer (NK) cells as well as T-helper cells are immune cells that frequent the uterine lining. They produce growth factors known as cytokines that regulate orderly implantation of the embryo and facilitate placentation (development of a functional placenta, the baby’s life line).There are two varieties of uterine cytokines: a) TH-2 (humoral) cytokines that promote permeation of the uterine wall by the embryo’s trophoblast (“root system and, b) TH-1 (cellular) cytokines that oppose trophoblastic proliferation and permeation of the uterine wall by culling interstitial trophoblastic cells. Orderly implantation and formation of a functional placenta (lifeline of the baby) requires that TH-1 and TH2 activity be in equilibrium
There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).
•Autoimmune IID. Here, there is often a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g. Hashimoto’s hypothyroidism) etc. Autoimmune IID also occurs in about one third of cases of endometriosis, regardless of severity.
•Alloimmune IID. Here uterine NK cell activation results from uterine exposure to an embryo derived through fertilization of an egg by a spermatozoon which shares certain genetic (HLA/DQ alpha)characteristics with that of the mother or embryo recipient.
In both autoimmune and alloimmune IID, the end point is an excessive NKa/CTL, TH-1 release that damages the embryos trophoblast, resulting in failed implantation or early pregnancy loss.
It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the degree of NK cell activation (cytotoxicity) that matters. In fact, there are certain conditions (such as with endometriosis) in which the NK cell blood concentration is normal or well below normal and NK cell activation is markedly increased.
There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or TH-1 and TH-2 cytokines have been used with some success. However, use of the K-562 target cell test remains the gold standard. With this test, NK cells are isolated from the woman’s blood using Flow Cytometry and are incubated in the presence of specific “target cells”. These are then incubated together. The percentage (%) of “target cells” killed through exposure to NKa/CTL-TH1 cytokines is then quantified.
Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably. I have for 20 + years been working with Reproductive Immunology Associates (RIA) in Van Nuys, CA and preferentially recommend them to my patients.
There exists a pervasive but blatant misconception on the part of many, that the addition of IL/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 several days 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.
It is very regrettable that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.
Hey Dr
I am 31 yrs ,and by a medical mistac i had lost parts of my ovaries that i was PCOS pateint and my doctor lead to OHHS ended by partial bilateral oopherectomy
However i wanna to know how much the chance for me to get ovum from my rest ovaries with just AMH =0.125
Plz give me hope
Yes! If there is residual ovarian tissue, given your young age, it is worth a try.
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”.
Women who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the effect of DOR, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can in my opinion, make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.I try to avoid using such protocols/regimes (especially) in women with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy
Please visit my new Blog on this very site, https://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.
• 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 Approach
• 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.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• 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
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview
ANNOUNCEMENTS:
1.About my Retirement by mid-2018:
After > 30 years in the field of Assisted Reproduction (AR), the time has finally come for me to plan on retiring from full-time clinical medicine within a year. If you are interested in my medical services prior to my retirement, 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.
2.The 4th edition of my newest 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
Dr Sher do you recommend Gonal F or Follistim? Pregnyl or novarel?
Gonal F and Follistim are identical as are Pregyl and Novarel.
Geoff Sher
Hi Dr. Sher,
What factors (basal blood levels? percentage of follicles that respond to stims?, etc) tell you that someone is a “poor responder” to gonadotropins /DOR and needs to use the DOR protocols? What are the Poor Responder values (ex: AMH below xxx, antral follicle response below xxx % )?
Would you use DOR protocols on someone with normal basal levels but low follicle response to stims? Would it hurt to use a DOR protocol as a precaution?
Thank you!
An AMH of <1.5ng/ml is clear evidence of DOR. 1.5-2.0ng/ml is in the "gray zone" and over 2.0ng/ml is normal.The AFC can be subjective but <10 would concern me.
Geoff Sher
Hi Dr. Sher,
Thank you for your blog. It has been an amazing resource!
In my last cycle, I started off with 14 antral follicles but only half grew when stimulated (BCP 3 weeks, Gonal-F 225, Menopur 75, Ganirelix 250 Day 5).
For the next cycle, my doctor wants to use the same protocol, but increase the dosage of Gonal-F and Menopur to get more antral follicles to respond from the start.
Will increasing the dosage increase the percentage of antral follicles that grow or will it just make the 50% that grow grow even faster (thus making a short cycle)? What dosage of Gonal-F and Menopur would you use or is there another protocol you would recommend?
Thanks!
Age: 39
AMH: 7
FSH: 5-6
AFC: 8-14
I think that it would be reasonable to increase the dosage of gonadotropins, but in my opinion, that is not enough. You need the entire protocol for ovarian stimulation to be critically reviewed and revised.
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.
•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?
•Blastocyst Embryo Transfers Should be the Standard of Care in IVF
•Why did my IVF Fail
•My Retirement in the Year Ahead: A letter of Thanks From me to You!
ANNOUNCEMENTS:
1.About my Retirement by mid-2018:
After > 30 years in the field of Assisted Reproduction (AR), the time has finally come for me to plan on retiring from full-time clinical medicine within a year. If you are interested in my medical services prior to my retirement, 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.
2.The 4th edition of my newest 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