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.
I’m 41 (amh 2.03, afc 12) just did first round egg retrieval: (estrace prime) clomid 2 times day for first 5 days, 12 days of stims menopur 150 at night, follistim 300 at night, ganirelix beginning around day 5 taken once a day and twice a day at the end. Triggered with pregnyl and leuprolide. My numbers were beyond expectations: 17 eggs retrieved, 15 mature, 12 fertilized naturally, of those we had 2 reach day 5 blast (5AA both), 2 reached blast day 6 (5AB, 5BB) and 2 more day 7 (5BB, 6BB) when pgta tested all of them aneuploid (except one of the day 5 was low level mosaic). I’m concerned that the protocol perhaps affected the egg competence and wonder if I should switch clinics to do my next two insured rounds? All karyotyping is normal for myself and husband (he has no factors of concern) and I take coq10, fish oil, vitamin D and DHEA. Is this likely to be an age issue or could it be an issue with the stims protocol?
The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome. While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion, compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
A significant percentage of older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
Preferred Protocols for Controlled Ovarian Stimulation (COS):
•Long GnRH Agonist Protocols: The most prescribed protocol for agonist/gonadotropin administration is the so-called “long protocol”. An agonist (usually, Lupron) is given either in a natural cycle, starting 5-7 days prior to menstruation or is overlapped with the BCP for two days whereupon the latter is stopped and the Lupron, continued until menstruation ensues. The agonist precipitates a rapid rise in FSH and LH level, which is rapidly followed by a precipitous decline in the blood level of both, to near zero. This is followed by uterine withdrawal bleeding (menstruation) within 5-7 days of starting the agonist treatment, whereupon gonadotropin treatment is initiated (preferably within 7-10 days of the onset of menses) while daily Lupron injections continue, to ensure a relatively “low LH- environment”. Gonadotropin administration continues until the hCG trigger.
•Short (“Flare”) GnRH-agonist (GnRHa) Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “springboard effect” constitutes “a double-edged sword”. While it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients
•Long-Agonist/Antagonist Conversion Protocol (A/ACP): With a few (notable) exceptions I preferentially advocate this protocol for many of my patients. With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts, she supplants the agonist with a with 250 mcg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide). Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman’s own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation, a large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of testosterone can also have an adverse effect on endometrial growth. Also, since agonists might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.
•Agonist/antagonist conversion protocol with estrogen priming: Patients start their treatment cycle on a combined (monophasic) birth control pill-BCP (e.g., Marvelon, Desogen, Orthonovum 135 Low-Estrin…etc.) for at least 8-10 days (depending on individual circumstances), before commencing controlled ovarian stimulation for IVF. With this approach, a GnRH agonist (e.g. Lupron/Superfact/Buserelin/Decapeptyl etc.) is continued until menstruation ensues (usually 5-7 days after commencement of the GnRH-agonist). At this point, the GnRH-agonist is SUPPLANTED with 250mcg GnRH antagonist (e.g. Ganirelix/Cetrotide, Orgalutron) and daily estradiol(E2) “priming” commences using either E2 skin-patches or intramuscular estradiol valerate (Delestrogen) injections, twice weekly while continuing the administration of the GnRH antagonist. Seven (7) days after commencing the E2 skin patches or intramuscular Delestrogen, daily injections of recombinant FSH-(e.g., Follistim/Gonal-F/Puregon) + menotropin (e.g., Menopur) therapy begins.. This is continued at a modified dosage, along with E2 patches or Delestrogen injections) until the “hCG trigger”. The egg retrieval is performed 36 hours later.
There are a few potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress.
Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-threatening Severe Ovarian Hyperstimulation Syndrome (OHSS). The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly, we currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-protocol” approach.
•Short-GnRH antagonist protocols: The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles (i.e. the administration of 250mcg daily starting on the 6th or 7th day of stimulation with gonadotropins) may be problematic, especially in women over 39 yrs., women with diminished ovarian reserve (i.e. “poor responders” to gonadotropins), and women with PCOS. Such women tend to have higher levels of LH to start with and as such the initiation of LH suppression with GnRH antagonists so late in the cycle (usually on day 6-7) of stimulation fails to suppress LH early enough to avoid compromising egg development. This can adversely influence egg/embryo quality and endometrial development. As is the case with the “microflare” approach (see above) the use of GnRH antagonist protocols in younger women who have normal ovarian reserve, is acceptable. Again, for reasons of caution, and because I see no benefit in doing so, I personally never prescribe this approach for my patients. Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called “premature LH surge”, which is known to be associated with “follicular exhaustion” and poor egg/embryo quality. However the term “premature LH surge” is a misnomer and the concept of this being a “terminal event” or an isolated insult is erroneous. In fact, the event is the culmination (end point) of the progressive escalation in LH (“a staircase effect”) which results in increasing ovarian stromal activation with commensurate growing androgen production. Trying to improve ovarian response and protect against follicular exhaustion by administering GnRH antagonists during the final few days of ovarian stimulation is like trying to prevent a shipwreck by removing the tip of an iceberg.
•Short-GnRH-agonist (“micro-flare”) protocols: Another approach to COH is by way of so-called “microflare protocols”. This involves initiating gonadotropin therapy simultaneously with the administration of GnRH agonist. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release to augment ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double-edged sword” as the resulting increased release of FSH is likely to be accompanied by a concomitant (excessive) rise in LH levels that could evoke excessive production of male hormone by the ovarian stroma. The latter in turn could potentially compromise egg quality, especially in women over 39 years of age, women with diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS) – all of whose ovaries have increased sensitivity to LH. In this way, “microflare protocols” can potentially hinder egg/embryo development and reduce IVF success rates. While microflare protocols usually are not harmful in younger women and those with normal ovarian reserve, I personally avoid this approach altogether for safety’s sake. The follicles/eggs of women on GnRH-agonist “micro-flare protocols” can be exposed to exaggerated agonist-induced LH release, (the “flare effect”) while the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days following the initiation of stimulation with gonadotropins can likewise be exposed to pituitary LH-induced ovarian male hormones (especially testosterone). While this is not necessarily problematic in younger women and those with adequate ovarian reserve (“normal responders”) it could be decidedly prejudicial in “poor responders” and older women where there is increased follicle and egg vulnerability to high local male hormone levels.
•The “Trigger Shot”- A Critical Decision: The egg goes through maturational division (meiosis) during the 36-hour period that precedes ovulation or retrieval. The efficiency of this process will determine the outcome of reproduction. It follows that when it comes to ovulation induction, aside from selecting a suitable protocol for COS one of the most important decisions the clinician has to make involves choosing and implementing with logic and precision, the “trigger shot” by which to facilitate meiosis.
•Urinary versus recombinant hCG: Until quite recently, the standard method used to initiate the “trigger shot” was through the administration of 10,000 units of hCGu. More recently, a recombinant form of hCGr (Ovidrel) was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably at best only has 60%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should be doubled to 500 mcg, at which dosage it will probably have an equivalent effect on promoting meiosis as would 10,000 units of hCGu.
•The dosage of hCG used: Some clinicians, when faced with a risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so, the risk of developing critical OHSS will be lowered. It is my opinion that such an approach is not optimal because a low dose of hCG (e.g., 5000 units hCGu or 25omcg hCGr) is likely inadequate to optimize the efficiency of meiosis, particularly when it comes to cases such as this where there are numerous follicles. In my opinion a far better approach is to use a method that I first described in 1989, known as “prolonged coasting”
•Use of hCG versus a GnRHa (e.g., Lupron/Buserelin/Superfact) as the trigger shot: It has been suggested that the use of an “agonist ( Lupron) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome (OHSS) could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. It is for this reason that many RE’s prefer to trigger meiosis in this way (using an agonist-Lupron) rather than through the use of hCG. The agonist promptly causes the woman’s pituitary gland to expunge a large amount of LH over a short period of time and it is this LH “surge” that triggers meiosis. The problem with this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland of a given patient receiving an agonist trigger shot, especially if the woman was down-regulated using an agonist, or in cases where an antagonist was used to block pituitary LH release. For this reason, I personally prefer to use hCGu for the trigger, even in cases of ovarian hyperstimulation, with one important proviso…that she underwent “prolonged coasting” in order to reduce the risk of critical OHSS prior to the 10,000 unit hCGu “trigger”.
•Combined use of hCG +GnRHa This approach is preferable to the use of a GnRHa, alone. However, in my opinion is inferior to the appropriate and correct use of hCG, alone.
•The timing of the trigger shot to initiate meiosis: This should coincide with the majority of ovarian follicles being >15 mm in mean diameter with several follicles having reached 18-22 mm. Follicles of larger than 22 mm will usually harbor overdeveloped eggs which in turn will usually fail to produce good quality eggs. Conversely, follicles less than 15 mm will usually harbor underdeveloped eggs that are more likely to be aneuploid and incompetent following the “trigger”.
Severe Ovarian Hyperstimulation Syndrome (OHSS) and prolonged Coasting”
OHSS is a life-endangering condition that usually occurs in women undergoing COS where the blood E2 level rises to above 4,000pg/ml. The risk escalates to greater than 80% in cases where the E2 level rises above 6,000pg/ml. It rarely occurs in normally ovulating women or older (>39Y) women and is more commonly encountered in:
•Young women (under 30y) who have a high ovarian reserve (based upon basal FSH and AMH.
•Women with polycystic Ovarian Syndrome (PCOS)
•Non-PCOS women who do not ovulate spontaneously
The treating physician should be alerted to the possibility of hyperstimulation when encountering a woman who develops >25 ovarian follicles of 14mm-16mm in mean diameter, in association with a blood E2 level of above 2,5000pg/ml prior to the hCG “trigger”.
OHSS is a self-limiting condition. Its development is linked to the effect of hCG and thus does not occur until the “hCG trigger” is administered. In fact, there is virtually no risk of OHSS until the hCG “trigger” is administered.
“Prolonged Coasting” is a procedure I introduced in 1991. It involves abruptly stopping gonadotropin therapy while continuing to administer the GnRH agonist (e.g. Lupron, Buserelin) deferring the hCG “trigger” until the woman is out of risk (as evidenced by a fall in plasma estradiol level to below 2,500pg/ml).
It is important that “prolonged coasting” be initiated as soon as two or more follicles have attained a greater diameter than 18mm with at least 50% of the remaining follicles having attained 14-16mm. To start the process of “prolonged coasting” any earlier or any later, while it would still protect against the development of OHSS, would almost certainly result in compromised egg and embryo quality with ultimate failure of the IVF cycle. Simply stated, the precise timing of initiating the process is critical. Proper implementation of PC will almost always prevent OHSS without seriously compromising egg/embryo quality.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.
I strongly recommend that you visit http://www.SherIVF.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
•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.
•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)
•Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
•Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
•Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
•Egg Maturation in IVF: How Egg “Immaturity”, “Post-maturity” and “Dysmaturity” Influence IVF Outcome:
•Commonly Asked Question in IVF: “Why Did so Few of my Eggs Fertilize and, so Many Fail to Reach Blastocyst?”
•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
•Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of 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.
•IVF: Selecting the Best Quality Embryos to Transfer
•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 outcome: How Does Advancing Age and Diminished Ovarian Reserve (DOR) Affect Egg/Embryo “Competency” and How Should the Problem be addressed.
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ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.
If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).
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Geoff Sher
I’m 37 yo,BMI 40,hypothyroidism controled with levoth. Healthy otherwise.Previosly 3 years ago(at 34) I had 2 cycles of IVF with menopur225u plus gonal f 225u around 10and 11 days, where in each cycle 11 eggs,10mature,7 fertilize and 3embryos(total 6 embryos between the 2 cycles and 3 of them where healthy after PGS).This time with same husband, on menstrual period day 3 FSH<10,AMH-1.09and 7 AFC.I just had 1st cycle 10 days with menopur 225u plus Gonal F 225u daily and 11 days lupron microdose. From different U/S tech. 6 follicles: 20.8 20.5 16.5 15.8 and 2=11.5 on day of trigger with ovidrel.at retrieval 3 eggs where catch and 2 of then mature, none fertilized. My question is what is your opinion of my protocol and what would be a best approach for my next cycle? Thank you
My partner and I just had our first ER for rIVF. She has a good AFC, normal AMH 4, and is 30. She stimmed for 9 days on Follistim 300, Menopur 150 and cetrotide for 9 days. She had great follicle growth but there was concern for OHSS so they had her trigger with Lupron. Unfortunately many of the eggs didn’t mature and our retrieval was largely unsuccessful. Our REI has said it wasn’t successful due overall poor egg quality. Is this due to our protocol/trigger or another underlying issue?
Very respectfully,
The more likely explanation (in my opinion) for the poor egg quality, probably relates to the timing and type of “trigger”. Understandably, given concern for the severe consequences of OHSS, some doctors tend tgo “trigger” early so as to avoid follicle stimulation to get out of hand. Also while a Lupron “trigger” does reduce the risks to the woman, it often comes at a price…..at the expense of egg quality.
Ideal egg development sets the scene for optimal egg maturation that occurs 36-42h prior to ovulation or egg retrieval. Without prior optimal egg development (ovogenesis), egg maturation will be dysfunctional and most eggs will be rendered “incompetent” and unable upon fertilization to propagate viable embryos. In IVF, optimal ovogenesis requires the selection and implementation of an individualized approach to controlled ovaria stimulation (COS). Thereupon, at the ideal time, maturational division of the egg’s chromosomes (i.e. meiosis) is “triggered” through the administration of hCG or an agonist such as Lupron, which induces an LH surge. The, dosage and timing of the “trigger shot” profoundly affects the efficiency of meiosis, the potential to yield “competent (euploid) mature (M2) eggs, and as such represents a rate limiting step in the IVF process .
“Triggering meiosis with Urine-derived hCG (Pregnyl/Profasi/Novarel) versus recombinant hCG (Ovidrel): Until quite recently, the standard method used to “trigger” egg maturation was through the administration of 10,000 units of hCGu. Subsequently,, a DNA recombinant form of hCGr (Ovidrel)was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably only has 50%-70%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should best be doubled to 500 mcg at which dosage it will probably have an equivalent effect on promoting meiosis as would 10,000 units of hCGu. Failure to “trigger” with 10,000U hCGu or 500mcg hCGr, will in my opinion increase the likelihood of disorderly meiosis, “incompetent (aneuploid) eggs” and the risk of follicles not yielding eggs at egg retrieval (“empty follicles”). Having said this, it is my personal opinion that it is unnecessary to supplant hCGu with hCGr since the latter is considerably more expensive and is probably no more biopotent than the latter.
Some clinicians, when faced with a risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so the risk of critical OHSS developing will be lowered. It is my opinion, that such an approach is not optimal because a low dose of hCG (e.g., 5000 units, hCGu or 250mcg hCGr) is likely inadequate to optimize the efficiency of meiosis particularly when it comes to cases such as this where there are numerous follicles. It has been suggested that the preferential use of an “agonist (Lupron/Buserelin/Superfact decapeptyl) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. It is with this in mind that many RE’s prefer to trigger meiosis by way of an “agonist (Lupron) trigger rather than through the use of hCG. The agonist promptly causes the woman’s pituitary gland to expunge a large amount of LH over a short period of time and it is this LH “surge” that triggers meiosis. The problem with using this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland. For this reason, I personally prefer to use hCGu for the trigger, even in cases of ovarian hyperstimulation hyperstimulated, with one important proviso…that being that is she underwent “prolonged coasting” in order to reduce the risk of critical OHSS, prior to the 10,000 unit hCGu “ trigger”.
The timing of the “trigger shot “to initiate meiosis: This should coincide with the majority of ovarian follicles being >15 mm in mean diameter with several follicles having reached 18-22 mm. Follicles of larger than 22 mm will usually harbor overdeveloped eggs which in turn will usually fail to produce good quality eggs. Conversely, follicles less than 15 mm will usually harbor underdeveloped eggs that are more likely to be aneuploid and incompetent following the “trigger”.
So, although possible, T strongly doubt that the poor egg quality wqas due to an “intrinsic” egg problem. The protocol for ovarian stimulation needs to be adjusted and taylor designed to meed your wife’s needs.
Call Patti Converse (my assistant) at 702-533-2691 and set up a time for an online consultation with me to discuss your case in detail!
Good luck!
Geoff Sher
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ADDITIONAL INFORMATION:
Preventing Severe Ovarian Hyperstimulation Syndrome with “Prolonged Coasting”
Geoffrey Sher MD
My approach 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.
I do not use antagonists in high responders (e.g., PCOS) because it interferes with the assay of E2 (often causing the value to be understated), a valuable index in assessing risk for the development of severe/critical OHSS. I also do not believe in the agonist trigger to prevent OHSS. The reason is that the magnitude of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the oocyte aneuploidy index.
I am getting ready to start an FET with my last frozen embryo. I previously had one unsuccessful frozen embryo transfer. My clinic transfers on day 6 of progesterone. All the information I have been able to find suggests that frozen embryos should be transferred on day 5 of progesterone. What is the best day to transfer a frozen embryo?
Day 6 is in my opinion…best!
I recently had my second failed transfer, our embryos have been tested, lining is always 10+, I’ve done an ERA however we haven’t been able to get an embryo to implant. We are now preparing for another retrieval but it seems as though the main issue we have is implantation. What are test that I can ask for my doctor to run? What are other suggestions as far as next steps?
There can be little doubt that embryo “incompetency” is by far the most important cause of IVF failure and that in >60% of such cases failure is attributable to numerical chromosomal irregularities (aneuploidy) of the embryo , which in turn is most commonly due to egg (rather than sperm) abnormalities. However, in about 20% of cases, the cause is due to “implantation dysfunction” rather than egg/embryo “incompetence”. It follows that in the pursuit of optimizing IVF outcome the clinician has profound responsibility to meticulously focus on all known variables that have the potential to adversely affect egg/embryo competency (e.g. maternal age ovarian reserve and the protocol used for ovarian stimulation), as well as those that can impact embryo implantation e.g. anatomical and/or immunologic) This article addresses the impact of embryo implantation. This is especially relevant in cases of “unexplained” IVF failure, Recurrent Pregnancy Loss (RPL) and in cases where the woman has a personal or family history of autoimmune diseases. Doing so, will not only go a long way towards maximizing the chance of pregnancy but will enhance the quality of placentation, thereby promoting the noble objective of optimizing the quality of life after birth.”
IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs , is better than 1:3. However, there is still a wide variation from program to program with live birth rates, ranging from 20% to near 50%. Based upon these statistics, the majority of women undergoing IVF in the United States will require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. In my opinion, this is far from being accurate. In fact, other factors such as variations in patient selection, the failure to implement individualized protocols for ovarian stimulation or to identify and address, anatomical and immunologic factors that can influence embryo implantation, are at least equally important.
Causes of implantation dysfunction:
•Anatomical abnormalities in the uterine cavity (polyps/scarring/internal fibroids)
Several studies performed both in the United States and abroad have confirmed that a dye X-Ray or hysterosalpingogram (HSG) will fail to identify small endouterine surface lesions in >20% of cases. This is significant because even small lesions have the potential to adversely affect implantation. Hysteroscopy is the traditional method for evaluating the integrity of the uterine cavity in preparation for IVF. It also permits resection of most uterine surface lesions, such as submucous uterine fibroids (myomas), intrauterine adhesions (synechiae) and endometrial or placental polyps. All of these can interfere with implantation by producing a local “inflammatory- type” response similar in nature to that which is caused by an intrauterine contraceptive device. Hysterosonography (syn HSN/ saline ultrasound examination) and hysteroscopy have all but supplanted HSG to assess the uterine cavity in preparation for IVF. HSN which is less invasive and far less expensive than hysteroscopy involves injection of a small amount of a sterile saline solution is injected into the uterine cavity, whereupon a vaginal ultrasound examination is performed to assess the contour of the uterine cavity.
•Endometrial Thickness: As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.
More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”. Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.
A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.
The main causes of a “poor” uterine lining are:
1.Damage to the basal endometrium because of:
a.Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
b.Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
c.Insensitivity of the basal endometrium to estrogen due to:
d.Prolonged, over-use/misuse of clomiphene citrate
2.Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
3.Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
4.Reduced blood flow to the basal endometrium: Examples include.
5.Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
6.Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).
Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.” Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening. Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects. It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).
•Immunologic Implantation Dysfunction ((IID):
Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.
The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.
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).
DIAGNOSIS
Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:
a.Unexplained or recurrent IVF failures
b.Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
c.Recurrent Pregnancy Loss (RPL)
d.Endometriosis
e.A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.
Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:
1.ACTIVATED UTERINE NATURAL KILLER CELLS (NKa):
Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.
Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).
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 NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but 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 through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.
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.
There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration… in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.
Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka. But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
2.ANTIPHOSPHOLIPID ANTIBODIES:
Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.) as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects. We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)]. More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane. It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:
a.The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
b.Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
c.Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.
3.ANTITHYROID ANTIBODIES: (ATA).
A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).
Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies.
The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.
It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.
Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in `reproductive performance in such cases.
The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment
There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).
AUTOIMMUNE, IID:
Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity. Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.
When it comes to treating NKa in IVF cases complicated by autoimmune implantation dysfunction, the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14 days prior to PGT-normal embryo transfer and repeated once more (only), as soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s) in women under 39Y (who have normal ovarian reserve) is approximately 65%.
ALLOIMMUNE, IID: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.
Partial DQ alpha/HLA match: Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.
Total (complete) DQ alpha Match: Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished. Several instances in our experience have required the use of a gestational surrogate.
TEATMENT OF IID:
The mainstay of treatment involves the selective use of:
a.Intralipid (IL) infusion
b.IVIg therapy
c.Corticosteroids (Prednisone/dexamethasone)
d.Heparinoids (Lovenox/Clexane)
Intralipid (IL) Therapy: IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.
It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.
Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL). IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.
Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.
It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.
Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL). IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.
Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression? Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.
oIVIg Therapy: Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.
oCorticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.
oHeparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)
oWhat About Baby Aspirin? In my opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.
oTH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.
oLeukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.
oAlternative approaches which in my opinion still lack confirmation of efficacy, include the following:
a.The use of the endometrial receptivity array (ERA) to determine the ideal window of implantation
b.Granulocyte Stimulating Factor (Neupogen)
c. Uterine plate rich plasma (PRP) for uterine washes
d.Endometrial flushing with hCG solution
e.Endometrial scratch
I strongly recommend that you visit http://www.SherIVF.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.
•A Fresh Look at the Indications for IVF
•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.
•Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
•IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
•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
•Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
•IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
•Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
•Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
•Genetically Testing Embryos for IVF
•Staggered IVF
•Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
•Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
•IVF: Selecting the Best Quality Embryos to Transfer
•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
•Endometrial Receptivity Array (ERA): Is There an actual “There, There”?
•IVF Failure and Implantation Dysfunction:
•Diagnosing and Treating Immunologic Implantation Dysfunction (IID)
•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!
•Endometrial Thickness, Uterine Pathology and Immunologic Factors
•Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
•A Thin Uterine Lining: Vaginal Viagra is Often the Answer (update)
•Cervical Ureaplasma Urealyticum Infection: How can it Affect IUI/IVF Outcome?
•The Role of Nutritional Supplements in Preparing for IVF
•The Basic Infertility Work-Up
•Defining and Addressing an Abnormal Luteal Phase
•Male Factor Infertility
•Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
•Hormonal Treatment of Male Infertility
•Hormonal Treatment of Male Infertility
•Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
•Endometriosis and Infertily
•Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
•Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
•Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
•Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
•Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
•Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!IUI-Reflecting upon its Use and Misuse: Time for a Serious “Reality Check
•Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
•Clomiphene Induction of Ovulation: Its Use and Misuse!
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.
If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).
PLEASE SPREAD THE WORD ABOUT SFS!
Geoff Sher