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by Dr. Geoffrey Sher on December 1, 2015

You are not alone. Dr. Sher is here to answer your questions and support you.

If you would like to schedule a one on one Skype, telephone, or in person consultation with Dr. Sher, please fill out the form on the right and our team will get you scheduled right away.

Dear Patients,

I created this forum to welcome any questions you have on the topic of infertility, IVF, conception, testing, evaluation, or any related topics. I do my best to answer all questions in less than 24 hours. I know your question is important and, in many cases, I will answer within just a few hours. Thank you for taking the time to trust me with your concern.

– Geoffrey Sher, MD

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  • KB - November 13, 2018 reply

    Got PGS result classification as “Undetermined Safety or Reproductive Potential”. This embryo demonstrated a 67.4Mb duplication on the long arm of chromosome 9 (9q21.11q34.3) in the mosaic range and a 37.7Mb duplication on the long arm of chromosome 10 (10q23.33q26.3) in the mosaic range.”

    The genetic counselors never specified what type of mosaic embryo this is. Is it safe to transfer this type with duplicate Chromosomes 9 & 10?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 14, 2018 reply

    I personally would not recommend a transfer where there are 2 or more chromosomes affected.

    Human embryo development occurs through a process that encompasses reprogramming, sequential cleavage divisions and mitotic chromosome segregation and embryonic genome activation. Chromosomal abnormalities may arise during germ cell and/or pre-implantation embryo development, and represents a major cause of early pregnancy loss. About a decade ago, I and an associate, Levent Keskintepe Ph.D. were the first to introduce full embryo karyotyping (identification of all 46 chromosomes) through preimplantation genetic sampling (PGS) as a method by which to selectively transfer only euploid embryos (i.e. those that have a full component of chromosomes) to the uterus. We subsequently reported on a 2-3 fold improvement in implantation and birth rates as well as a significant reduction in early pregnancy loss, following IVF. Since then PGS has grown dramatically in popularity such that it is now widely used throughout the world.
    Most IVF programs that offer PGS services, require that all participating patients consent to all their aneuploid embryos (i.e. those with an irregular quota of chromosomes) be disposed of. However, there is now growing evidence to suggest that following embryo transfer, some aneuploid embryos will in the process of ongoing development, convert to the euploid state (i.e. “auto correction”) and then go on to develop into chromosomally normal offspring. In fact, I am personally aware of several such cases occurring within our IVF network. So clearly, by summarily discarding all aneuploid embryos as a matter of routine we are sometimes destroying some embryos that might otherwise have “autocorrected” and gone on to develop into normal offspring.
    Thus by discarding all aneuploid embryos we, in so doing, might be denying some women the opportunity of having a baby. This creates a major ethical and moral dilemma for those of us that provide the option of PGS to our patients. On the one hand, we strive “to avoid knowingly doing harm” (the Hippocratic Oath) and as such would prefer to avoid or minimize the risk of miscarriage and/or chromosomal birth defects and on the other hand we would not wish to deny patients with aneuploid embryos, the opportunity to have a baby.
    The basis for such embryo “auto correction” lies in the fact that some embryos found through PGS-karyotyping to harbor one or more aneuploid cells (blastomeres) will often also harbor chromosomally normal (euploid) cells (blastomeres). The coexistence of both aneuploid and euploid cells coexisting in the same embryo is referred to as “mosaicism.” Many such mosaic embryos will In the process of subsequent cell replication convert to the normal euploid state (i.e. autocorrect)
    It is against this background, that an ever increasing number of IVF practitioners, rather than summarily discard PGS-identified aneuploid embryos are now choosing to cryobanking (freeze-store) certain of them, to leave open the possibility of ultimately transferring them to the uterus. In order to best understand the complexity of the factors involved in such decision making, it is essential to understand the causes of embryo aneuploidy of which there are two varieties:
    1. Meiotic aneuploidy” results from aberrations in chromosomal numerical configuration that originate in either the egg (most commonly) and/or in sperm, during preconceptual maturational division (meiosis). Since meiosis occurs in the pre-fertilized egg or in and sperm, it follows that when aneuploidy occurs due to defective meiosis, all subsequent cells in the developing embryo/blastocyst/conceptus inevitably will be aneuploid, precluding subsequent “auto correction”. Meiotic aneuploidy will thus invariably be perpetuated in all the cells of the embryo as they replicate. It is a permanent phenomenon and is irreversible. All embryos so affected are thus fatally damaged. Most will fail to implant and those that do implant will either be lost in early pregnancy or develop into chromosomally defective offspring (e.g. Down syndrome, Edward syndrome, Turner syndrome).
    2. “Mitotic aneuploidy” occurs when following fertilization and subsequent cell replication (cleavage), some cells (blastomeres) of a meiotically euploid early embryo mutate and become aneuploid. This is referred to as mosaicism. Thereupon, with continued subsequent cell replication (mitosis) the chromosomal make-up (karyotype) of the embryo might either comprise of predominantly aneuploid cells or euploid cells. The subsequent viability or competency of the conceptus will thereupon depend on whether euploid or aneuploid cells predominate. If in such mosaic embryos aneuploid cells predominate, the embryo will be “incompetent”). If (as is frequently the case) euploid cells prevail, the mosaic embryo will be “competent” and capable of propagating a normal conceptus.
    Since some mitotically aneuploid (“mosaic”) embryos can and indeed do “autocorrect’ while meiotically aneuploid embryos cannot, it follows that an ability to differentiate between these two varieties of aneuploidy would be of enormous clinical value. Since some mosaic embryos can “autocorrect” and even go on to propagate a viable baby, the ability to confirm that aneuploidy is mitotic (potentially reversible) would provide a strong argument in favor of preserving certain aneuploid embryos for future dispensation. Unfortunately however, there is presently no microscopic or genetic test that can reliable differentiate between meiotic and mitotic aneuploidy.
    Aneuploidy, whether meiotic or mitotic in origin involves the addition of one or more chromosomes to a given pair in human embryos. Certain aneuploidies involve only a single, chromosome pair (simple aneuploidy) while others involve more than a single pair (i.e. complex aneuploidy). Evidence suggests that complex aneuploidy, whether meiotic or mitotic in origin is almost always lethal while all forms of meiotic aneuploidy are permanent. Some aneuploidies, especially those that involve addition of a chromosome to any pair (trisomy) will at times progress to clinical pregnancies (e.g. trisomy 15, 18, 21 or when the sex chromosomes are involve). And as stated previously, most aneuploid embryos, should they attach, will miscarry or result in a chromosomally defective offspring.
    On the other hand, some aneuploid embryos have one chromosome (in a given pair) missing (i.e. monosomy). Aside from monosomy involving absence of the Y-sex chromosome (i.e. XO) which can resulting in a live birth (Turner syndrome) all other monosomies involving autosomes (non-sex chromosomes) are lethal and will not result in viable offspring.
    Since it is presently not possible, without removing more than 1 cell from an embryo (a very traumatic event) to differentiate between meiotic and mitotic aneuploidy, it follows that making a diagnosis of embryo aneuploidy does not allow for identification of mosaic embryos for transfer. This is especially true when it comes to trisomic embryos that can and sometimes do, propagate chromosomal birth defects such as Down syndrome. It is important to bear in mind that the transfer of trisomic embryos (whether due to meiotic or mitotic aneuploidy) can result in miscarriage or a birth defect. This makes any attempt to transfer such embryos to the uterus fraught with risk and in my opinion, ill advised. Conversely, since true meiotic autosomal monosomic embryos cannot propagate viable pregnancies, performing embryo transfer in such cases in the hope that the aneuploidy is mitotic (mosaic) in origin and will spontaneously “ auto correct”, is a rational consideration. Needless to say, such action would require full disclosure, and the execution of a detailed, informed consent agreement which would include an expressed commitment to undergo prenatal genetic testing aimed at excluding a chromosomal defect in the developing baby and/or a willingness to terminate the pregnancy should a serious birth defect be diagnosed.
    Since it is meiotic rather than mitotic aneuploidy that is invariably lethal and given that meiotic aneuploidy originates in the egg, it is my belief that the closer to fertilization that embryo biopsy is done for PGS, the more likely it is that any aneuploidy detected, will be meiotic in origin. The longer you wait thereafter, the greater the likelihood that with repeated mitotic division, mutational changes will result in mitotic aneuploidy (mosaicism). This is why I strongly believe embryo biopsies should be performed on day 2-3 post fertilization rather on day 5-6 days (the blastocyst stage).”

    Good luck!

    Geoff Sher

  • Gary - November 13, 2018 reply

    Thank you for your forum.
    What is your thought on embryos with vacuoles? We have a frozen day 6 embryo that is high level mosaic with an extra chromosome on 20 and has vacuoles. Do vacuoles plus high level mosaic 20 indicate this embryo should not be transferred?
    Thank you.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    I would still transfer it!

    Geoff Sher

  • Zara - November 13, 2018 reply

    Hi I m on decapeptyl from day 21 of my previous cycle now for 12 days for long protocol of my 5th icsi cycle…Have not been on ocp but my periods delayed than usual…is it due to decapeptyl??Natural pregnancy seems v unlikely.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    It s possible that you have an agonist-induced ovarian cyst. Have an US and blood estradiol to determine same.

    Good luck!

    Geoff Sher

  • nuria - November 13, 2018 reply

    Many thanks for your comments. what have done is IVF not an IUI, in my natural cycle too obtain my egg and the only medicament used was ganirelix once my follicule was 16mm and estradiol 100 in day 12, however the next two days estradiol was 47, progesterone 0.44 and lh 4, so i didnt ovulated but i think was the effect of ganirelix. i have normal cycles of 28 days and apparently not prematurely lh high levels. i had 3 more natural IVF in the last months: one cycle they got one natural egg (after ovitrelle and ganirelix in day 12 when estradiol 267_ result in one embryo and transfer but not pregnant), another cycle ovulated espontaneously after ovitrelle and ganirelix in day 14 when estradiol 330 and another cycle they administered ganirelix in day 9 and drop estradiol however lh was normal, I think they are doing something wrong.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Here is the approach I take in women, who have “adequate” ovarian reserve.
    My advice is to use a long pituitary down regulation protocol starting on a BCP, and overlapping it with Lupron 10U daily for three (3) days and then stopping the BCP but continuing on Lupron 10u daily (in my opinion 20U daily is too much) and await a period (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst and simultaneously, the Lupron dosage is reduced to 5U daily to be continued until the hCG (10,000u) trigger. An FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is started with the period for 2 days and then the gonadotropin dosage is reduced and a small amount of menotropin (Menopur—no more than 75U daily) is added. This is continued until US and blood estradiol levels indicate that the hCG trigger be given, whereupon an ER is done 36h later. I personally would advise against using Lupron in “flare protocol” arrangement (where the Lupron commences with the onset of gonadotropin administration.
    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.
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
    • Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
    • A personalized, stepwise approach to IVF
    • “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Lauren - November 13, 2018 reply

    Many thanks for answering all of our questions. It’s a huge relief to feel heard. Thank you. My question is: I am 37, female. I had a surgery to remove uterine polyps 6 months ago and that went fine. My HSG was normal. My FSH level is rather consistently around 12. I’m about to start my third natural cycle IUI with Ovidrel injected 36 hours before the procedure. All other hormone aspects come back normal, husband also normal numbers. I understand that the polyps likely interfered with getting pregnant for the past two years we’ve been trying. I have good follicle count relatively, between 8 to 12 on each ovary about. I have very normal periods, right on time each month. Is there some route we are not exploring or is there some kind of outside the box thinking I need to pursue? I know that my FSH level is not great. Is this hopeless? Thanks so much, in advance.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    I do not believe that natural cycle IUI has any real benefit. In my opinion, IUI should be combined with ovarian stimulation.

    It is hard for me to believe that more than three decades have flown by since I first introduced intrauterine insemination into the clinical arena (Journal of Fertility & Sterility, April, 1984). At that time and for more than 2 decades thereafter, I held the strong belief that IUI would provide a less expensive, safe and equally successful alternative to IVF in cases where the woman had at least one (1) patent Fallopian tube…. How wrong I was! In my defense however, let me say that in the 1980’s and 90’s the reported National IVF success rate was under 15% while y IVF success rates are now often 4 or even 5 times higher.

    Today I believe that IUI is being over-used, is not nearly as beneficial as I once thought and that there are (often ignored) serious down-sides to its use. Here is one important example: Women who fail to ovulate or ovulate dysfunctionally, often respond to controlled ovarian stimulation (COS) by the releasing (ovulating) of several eggs at a time. Since unless IVF is used, it is not possible to control/regulate the number of embryos reaching the uterus, the risk of high-order multiple pregnancies (triplets or greater) is far greater with IUI. And, multiple pregnancies (especially triplets or greater) carry a very high maternal and neonatal risk.

    Here are a few of the misperceptions about the use of IUI:

    1) IUI is a “cost saver”. However, given the fact that IVF is at least 3-4 times more likely to be successful, when one looks at cost per baby (rather than cost per procedure) this turns out to be a fallacy. But cost also comes in the form of emotional currency and this needs to be measured in terms of the much lower chance of success with IUI.
    2) “IUI is less invasive than IVF”… ….True! However aside from the surgical egg retrieval (which is a very safe procedure in the right hands/setting), IUI with gonadotropins requires largely the same drugs, preparation and monitoring as does IVF and the success rate is several fold lower than IVF.
    3) The use of oral Clomiphene Citrate for IUI- COS provides the same success rates as does Gonadotropin-IUI. This is absolutely incorrect. In fact the IUI success rate with clomiphene is about 30% lower than when gonadotropins are used.
    4) Natural cycle IUI has benefit: This is only true when frozen donor sperm is used for inseminations and in the isolated cases where there is non-immunologic cervical hostility to sperm. In all other cases, COS is needed to improve success.
    5) IUI can be used in cases of Embryo Implantation Dysfunction: Given the complexity of treatment is in cases where a thin uterine lining, significant uterine anatomical disease or immunologic implantation dysfunction (IID) prevents a healthy pregnancy, it is my opinion that IVF is the preferred primary approach.
    6) IUI can supplant or replace IVF in all cases where there is patency of at least 1 Fallopian tube. However, contrary to popular belief, there is no evidence that IUI improves pregnancy potential in cases of:
    a. Moderate or severe male factor infertility
    b. Endometriosis with patent Fallopian tubes. Since inseminating sperm does not overcome the main impediment to fertility, i.e., a “toxic” peritoneal factor that compromises sperm penetrating the egg envelopment).
    c. Older women (over 40y) where the IUI pregnancy yield is only about 2% per treatment cycle.

    Upon Honest Reflection:
    Unfortunately, too many physicians who should (and alas often do) know better, still liberally recommend IUI preferentially in cases of moderate or severe male infertility, older infertile women or those with diminished ovarian reserve (DOR), cases of endometriosis or where there is clear evidence of an anatomical r immunologic implantation issue. Such women would be much better advised to go directly to IVF but find themselves attracted to what they erroneously consider to be a much lower cost alternative.

    Then there is the fact that many infertile patients, erroneously believing that IUI is less risky that IVF, provides an equivalent chance of success, and comes at a much lower price tag, put undue pressure on their physicians to first try the former several times before resorting to the latter.

    To make matters worse, many misguided insurance providers (purely for economic reasons) demand that their female clients who have at least 1 patent Fallopian tube, first undergo several unsuccessful attempts at IUI before becoming eligible for IVF. And they often take this position regardless of cast iron indications that IVF should be the primary treatment of choice.

    In summary, it is my opinion that IUI is presently an over-prescribed treatment. As such, we as physicians need to rethink the basis upon which we recommend IUI and educate our patients app

    Geoff Sher

    Lauren - November 13, 2018 reply

    Thanks for your response. I had read your thoughts on IUI being over prescribed in another post and that’s what caught my attention. Since I ovulate regularly, it seems that ovarian stimulation plus IUI wouldn’t be recommended either according to the above response. Can you please suggest other options to consider? Does it all come down the FSH number being 12? Is IVF my only option? Thank you.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Hi Lauren,

    I would be happy to advise you but to do so authoritatively, I would need a great deal more information.

    Please call Tina at 800-780-7437 and set up a Skype consultation with me to discuss.

    Geoff Sher

  • Mae - November 13, 2018 reply

    Dr. Sher,
    Would you ever consider transferring a normal embryo with a mosaic one? Would there be more risks to losing the normal embryo as well? Please let me know your thoughts. Thank you

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Absolutely I would do so!

    Geoff Sher

    Mae - November 13, 2018 reply

    Thank you! My doctor is worried it will put our normal embryo at risk. Is there any research I can point her to?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Hi Mae,

    I need you to re-post your original question along with this one so that I have the context!

    Thanks!

    Geoff Sher

  • DS - November 13, 2018 reply

    Are there any exceptions to the rule where a woman is releasing an egg during the 7th, 8th or 9th month of pregnancy?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Ovulation does not occur during pregnancy

    Geoff Sher

  • Jen w - November 12, 2018 reply

    Hi Dr. Sher
    We are exactly 5 weeks along after Ivf with fresh 5 day transfer. Today we had an ultrasound and was able to see a 5mm gestational sac with a nice yolk sac inside.
    However my blood work wasn’t as great. My hcg 4 days ago was 487
    And today it was 1479 so it didn’t double within 48 hours more like 59 hours. My dr said because my ultrasound looked great she’s not overly concerned but I’m freaking out. Should I be worried?
    My next appointment is an ultrasound in 9 days should I request to come in sooner for another beta? Or just relax and go by the ultrasound? Would u advise your patient that they should be concerned? Thankyou

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    I would agree with your RE.

    Geoff Sher

  • Amber - November 12, 2018 reply

    Dr. Sher,
    I had a 5 day FET using donor egg on 11/1 (same donor egg first fresh transfer resulted in live birth). Grade 5AA, partially hatched before transfer. On 11/9 my HCG was only 6; assuming chemical pregnancy. My clinic told me to continue PIO/estrace. On 11/12 (3 days later), it’s 24. Should I be concerned about ectopic, or is there another reason why the level might be rising? Thank you for your time; I very much appreciate it.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 13, 2018 reply

    Too early to know.

    Geoff Sher

  • Maria - November 12, 2018 reply

    Hi Dr. Sher,
    Today I will be taking my 10,000U trigger shot and I have 11 follicles measuring: 22, 21, 20, 19, 18, 18, 17, 16, 16, 15, 14, 11, 11, 10
    I am hoping by adding the extra 5,000U of trigger they will come out mature, as last IVF produced only 2 mature out of 10, only using 5,000U. With these sizes, do you think I am capable of getting a good number of mature eggs now that I am taking the 10,000U?

    Maria - November 12, 2018 reply

    I will also mention, my estradiol level yesterday (I don’t yet have today’s number) was 3759

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    Copy!

    Geoff Sher

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    I would hope for 8-10 mature eggs!

    Good luck!

    Geoff Sher

  • nuria - November 12, 2018 reply

    only add that i have almost 37 years

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    Copy!

    Geoff Sher

  • nuria - November 12, 2018 reply

    hello dr sher,
    I Know that you dont do ivf in natural cycles, however i am very confused with my clinic and I would like to be helped related to this. my natural cycle have just been cancelled because in day 12 when follicule was in 16 mm they administered ganirelix to avoid ovulation and my levels of estradiol dropped from 100 to 57 in two days of that, im thinking if ganirelix should be admimistered together with gonadotropins. in other natural cycle they admimistered it only one day together with ovitrelle when E2 267 and 18 mm of follicule and got mature egg and embryo transfer although not pregnant. I Have a 1 year old baby by ivf in the first transfer with donor sperm because my husband has cromosome translocation, i had low reserve and now to the second baby in the the stimulated ivf obtained 1 egg but 1 good embryo also but not pregnant, and this is why im now with natural cycle, i have almost 37 years.. Many thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    What you likely experienced is in my opinion, premature luteinization, something quiote common in women who have DOR and (again) in my opinion, more likely with NC-IVF, especially when conducted in such cases.

    Premature luteinization (“premature LH surge”) occurs when prior to the planned initiation of the hCG trigger, a progressive rise in LH, irreversibly compromises follicle and egg development and maturation. It is not a sporadic isolated event. It comes as a culmination of a series ovarian events, occurring mostly in susceptible women (i.e. usually older women and those with diminished ovarian reserve. It is more likely to occur when the protocol used for ovarian stimulation has failed to maintain LH activity at a low level prior to and throughout the ovarian stimulation process. Once it occurs in any given stimulation cycle it cannot be switched off by changing the stimulation in progress or by administering GnRH antagonists (e.g. Ganirelix/Cetrotide/Orgalutron) midway in the cycle in the hope that this could rescue the eggs under development. It is my opinion, once premature luteinization commences, the cycle is doomed and outcome is doomed to fail. The condition increases the likelihood of premature ovulation, failed release of eggs during needle-guided egg retrieval (so called “empty follicle syndrome” and the incidence of egg/embryo “incompetence” (chromosomal aneuploidy).
    This situation is most commonly seen in older women and in women who have severely diminished ovarian reserve. In many cases its effect can be prevented through implementation of strategic and individualized protocols for controlled ovarian stimulation (COS) coupled with optimizing the type, timing and dosage of the “hCG trigger shot.”
    Normally, following optimal ovarian stimulation, the “trigger shot” is given for the purpose of it initiating meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).
    Older women, and women with diminished ovarian reserve, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.
    Women with the above mentioned conditions often have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”
    The developing eggs of women who have increased LH activity (older women, and women with diminished ovarian reserve) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrozole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.
    The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG or Ovidrel can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

    In my opinion, against the backdrop of age and diminished ovarian reserve (DOR), the protocol used for ovarian stimulation is one of the most important drivers of egg “competence” (quality) and the number, yielded.
    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, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

    • 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

    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Ayesha - November 12, 2018 reply

    Dear Dr,
    First of all i would like to appreciate your constant support.
    I wanted to discuss my anomaly report with you. I have a anterior low placenta, 29.1 mm away from internal OS.

    BPD: 51.4 mm
    Hc: 193 mm
    Fl: 37.6 mm
    FAC: 173.1 mm
    FHR: 148 bpm
    EFBW: 476 grams
    Mean gestational age: 21 weeks 6 days
    Cervical canal: 37 mm. Os closed.

    Can you kindly tell if there is anything to worry about? Is low lying placenta a problem ?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    In my opinion this will not likely be a problem. As the uterus enlarges and the lower uterine segment develops, it will likely move further from the cervix and be fine.

    Good luck!

    Geoff Sher

  • Humera - November 12, 2018 reply

    I’ve missed my periods out every 3 months for past few years but this time they’re really light pink only when wiping with a tissue really worried about cancer and I’m 23 pls can you help me out had my thyroid and hormones everything normal

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    This is not an indication of “cancer”. It is likely hormonal dysfunction.

    Geoff Sher

  • Katie - November 12, 2018 reply

    Hi Dr. Sher, is there any potential benefit or harm to taking HGH when producing lots of eggs? I have done 5 IVF cycles, 4 failed. I am 33 with MRKH and have retrieved 14-32 eggs each cycle with lost of immatures and almost no blasts. I have a higher AMH indicating that PCOS may be a factor but they have not confirmed that I have PCOS and generally have cyst free ovaries. Looking for any way to increase egg quality. Many thanks!!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 12, 2018 reply

    In my opinion, HGH is not a factor.

    The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
    After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
    One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.
    Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).
    Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.
    The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
    The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.
    It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.
    The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those 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 in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).
    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.
    During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
    However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.
    It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.
    In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH
    It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.
    Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.
    Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here 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 “spring board effect” represents “a double edged sword” because 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 androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. 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 in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.
    Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
    The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases) can obviate this effect
    .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
    • 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.

    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Samta - November 11, 2018 reply

    Hello Dr SHER,

    I had 6 failed IUI and now planning for IVF. I’m confused on whether to go ahead with birth control pills protocol or not. I’m consulting at two clinics – one which follow birth control protocol and one which does not follow. My AMH level is 2.9 and FSH/LH all good. What is the benefit of using birth control pills ? Does it increase egg quality and more eggs retrieval ? Really appreciate if you can provide the response on this

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 11, 2018 reply

    Here is the protocol I advise for women, who have adequate ovarian reserve as is the case with you.
    My advice is to use a long pituitary down regulation protocol starting on a BCP, and overlapping it with Lupron 10U daily for three (3) days and then stopping the BCP but continuing on Lupron 10u daily (in my opinion 20U daily is too much) and await a period (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst and simultaneously, the Lupron dosage is reduced to 5U daily to be continued until the hCG (10,000u) trigger. An FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is started with the period for 2 days and then the gonadotropin dosage is reduced and a small amount of menotropin (Menopur—no more than 75U daily) is added. This is continued until US and blood estradiol levels indicate that the hCG trigger be given, whereupon an ER is done 36h later. I personally would advise against using Lupron in “flare protocol” arrangement (where the Lupron commences with the onset of gonadotropin administration.
    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.
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
    • Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
    • A personalized, stepwise approach to IVF
    • “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

    ADDENDUM:

    The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
    After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
    One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.
    Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).

    Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.

    The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
    The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.

    It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.

    The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those 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 in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).
    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.
    During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
    However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.

    It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.

    In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH

    It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.

    Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.

    Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here 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 “spring board effect” represents “a double edged sword” because 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 androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. 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 in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.

    Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
    The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases) can obviate this effect

  • Michelle - November 11, 2018 reply

    Hello Dr. Sher,

    I’m currently five weeks pregnant and I’ve been prescribed estrace 4 mg twice per day (8mg total per day) until 12 weeks of pregnancy. I’m wondering if this medication had been known to cause stomach troubles? I ask because in my last pregnancy I took baby aspirin until 20 weeks of pregnancy and I developed painful gastritis (possibly from the aspirin). I feel stomach pains after every meal now. In your opinion, could estrace be the culprit, and is it absolutely necessary during pregnancy? Having no known problems to carry a pregnancy, could I do without the estrace? (I’m also on prometrium orally and vaginally three times a day). Thank you for your help Dr. Sher.

    Michelle

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 11, 2018 reply

    I do not believe the stomach problem is linked to the use of oral estrace …but I guess anything is possible.

    Good luck!

    Geoff Sher

  • Kelly - November 11, 2018 reply

    Hi,
    I am 37 years old and have been found to have good fertility based on the test my specialty done, my husband had a sperm volume issue, we have undergone ICSI and also 2 natural cycles of embryo transfers.. my embryos are of grade 5AA but all failed, my last cycles I also had a scratch to see if this helps implantation, I am finding it difficult to understand why they are failing if my specialist has no concerns with my fertility, can you suggest anything for me as I’m about to go through a fresh cycles in the next months

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 11, 2018 reply

    Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
    It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
    1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
    2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
    We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
    3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
    4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
    a. A“ thin uterine lining”
    b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
    c. Immunologic implantation dysfunction (IID)
    d. Endocrine/molecular endometrial receptivity issues
    Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
    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.
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • 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
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • 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
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • 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
    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Terry - November 10, 2018 reply

    Dear Dr. Sher, Appreciate the fertility engagement at your website. My question up front: for someone of age 40 with regular cycles with the following details is Clomid (50 mg, taken days 5 to 10) advisable and importantly, does it improve egg quality? Any NIH studies you can cite would be very helpful.
    My numbers:
    – aged 40 with one miscarriage (MS) at aged 36, live birth at 37 and MS at 40. Pregnancy in all cases occurred with two months of trying. My husband has a solid sperm count.
    – completely healthy (no medication, good BMI, no medications, never taken alcohol/drugs/smoking). I am an academic researcher so have read about a dozen NIH posted papers on Clomid.
    – just started taking ubiquitol co-q10 (improved absorbance compound – pepper extract, see NIH study on this topic) for improved egg quality.
    – trying to conceive for four months now, however, I just realized that there is much ejaculate outside of me after intercourse which seems to be a big problem. I have discussed this with my husband. (I am from a conservative upbringing so did not think to address this sooner because it did not dawn on me.)

    I requested Clomid from my OBGYN. I am hesitant in taking it due to thinning of the lining but primarily because its effects are strong on processes in the ovaries but its benefits are not clear. However, I would take it if I saw studies supporting egg quality, for someone of my age.

    Thanks,
    Terry.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 11, 2018 reply

    I would definitely advise against clomiphene at 40y. I would also advise against IUI …see below.

    Induction of Ovulation With Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use

    Geoffrey Sher MD

    Clomiphene (syn; Clomid , Serophene) is by far the most widely prescribed agent for the induction of human ovulation for women who do not ovulate, those with dysfunctional ovulation and women with ”unexplained” infertility. When used in young women (who have adequate ovarian reserve) with these problems the viable pregnancy rate is reported as being between 6% and 10% per cycle of treatment. Aside from conventional ovulation induction, clomiphene has been used in preparing women for intrauterine insemination and even for IVF. I personally rarely prescribe clomiphene because across the board, success rates are significantly lower than when gonadotropin therapy is used. The main reasons for clomiphene’s popularity is its low cost, simplicity of use and the low risk of dangerous complications such as severe ovarian hyperstimulation syndrome (OHSS).
    Clomiphene treatment can be initiated at a dose of 50 mg (orally) daily for 5 days but it can be increased to as much as 200mg per day, starting on cycle 2, 3, 4, or 5. A spontaneous LH surge will usually follow within about 8-9 days of the last 50mg dosage. In some cases, 10,000U of hCG can be given as a trigger when there is at least one ovarian follicle of 18-20 mm in size. Routinely using the hCG trigger does tend to decrease pregnancy potential.
    Clomiphene works by inducing ovulation through its “antiestrogen effect” which, by blocking estrogen receptors in an area of the brain known as the hypothalamus, tricks the brain into “thinking” that estrogen levels are low. In response, the hypothalamus prompts the pituitary gland to release an exaggerated amount of follicle-stimulating hormone (FSH), which in turn stimulates the growth and development of ovarian follicles, ultimately resulting in a surge in the release of pituitary LH. About 38-42 hours later, ovulation occurs from one or more of the larger follicles. As the follicles grow, they release more and more estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene.
    There are several factors that need to be considered carefully before deciding to prescribe clomiphene to any woman:
    • Clomiphene citrate therapy is less effective than gonadotropin therapy and its efficacy declines with advancing age: Many infertile couples undergoing ovulation induction believe that the success rate using clomiphene citrate is equivalent to what we see in fertile couples trying to get pregnant on their own and to what is encountered when gonadotropins (Menopur/Follistim/Gonal-F and Puregon) are used. This is not the case. The truth is that the rate of conception with clomiphene therapy is actually about 30% lower than the natural fertility rate for normally ovulating women, and about 25% lower than when gonadotropin stimulation is used for ovarian stimulation in similar patients. Moreover, the discrepancy is further magnified with advancing maternal age, where in women under 35 years, the pregnancy rate with clomiphene treatment is about 10% per cycle, about 5% between 35 and 40 years and <2% for women in their early to mid-forties.
    • Clomiphene use should ideally be confined to younger women: Ideally the use of clomiphene should in my opinion be restricted to younger women (under 35 years) who have normal “ovarian reserve” (as assessed by basal blood FSH, and antimullerian hormone (AMH) levels). These are the women who are most likely to respond by producing multiple follicles. It is necessary that at least 3 sizeable follicles (>15mm) develop on clomiphene treatment, in order to override the “anti-estrogenic” effects of this drug and so insure adequate cervical mucus production as well as the development of a receptive endometrium.
    • Clomiphene should usually not be administered for more than 3 consecutive (back-to- back) cycles: If used back-to-back for more than 3 consecutive cycles, clomiphene is not only ineffective, but actually starts to function as a “relative” contraceptive! This is often is a shocking revelation to many women. Clomiphene’s anti-estrogenic effect is not confined to the hypothalamus. Any cells that have a high concentration of estrogen receptors will also be so affected. Needless to say, the cervical glands (that produce estrogenic mucus to facilitate sperm transport and the endometrial lining (endometrium) that thickens under the effect of estrogen are also highly vulnerable to a buildup of antiestrogen effects over successive back-to back cycles of clomiphene therapy. This why with >3 consecutive back-to back clomiphene cycles cervical mucus tends to thicken and dry up and the endometrium will thin, seriously reducing the likelihood of success. These anti-estrogenic manifestations require that following 3 back-to back clomiphene cycles of stimulation there be at least 1 resting (non-clomiphene treated) cycle, before doing a 4th cycle.
    • Clomiphene should not be used in older women or in women who have diminished ovarian reserve (DOR): With clomiphene stimulation, the release of pituitary FSH is always accompanied by the concomitant release of Luteinizing Hormone (LH). LH causes the ovary to produce male hormone (androgens) and testosterone. The production by the ovaries of a modest amount of testosterone would not present a problem. However, an excessive production of ovarian testosterone prejudices egg development and thus ultimately compromises embryo competency. Older women and women with DOR are the most vulnerable because they tend to have overgrowth of ovarian connective tissue (stroma/theca) which is the site where androgens are produced. The concentration of androgens is always much higher at the site of production (the ovaries) than in the peripheral blood (a dilution effect). Thus in older women and those with DOR, there will be excessive ovarian androgens that can compromise egg quality and thus ultimately reduce the chance of having a baby. The older the woman and/or the more severe the DOR, the greater this adverse effect is likely to be.
    • “Trapped” ovulation (LUF-Syndrome): About 20% of clomiphene cycles are associated with “trapped” ovulation (Luteinized Unruptured Follicle (LUF) Syndrome). This means that in spite of hormone changes suggesting that ovulation has occurred, the egg remains trapped in the ovary. Obviously this is not condusive to the establishment of a successful pregnancy.
    • Endometriosis is a “relative contraindication” to the use of clomiphene: Women with endometriosis (regardless of its severity) have” toxic factors” in their pelvic peritoneal fluid. Eggs, as they pass from the ovaries to the Fallopian tubes to reach the awaiting sperm, become exposed to these “toxins” which renders the egg envelopment (zona pellucida) resistant to sperm penetration. This reduces fertilization potential by a factor of at least 3 or 4. This means that if, in the absence of endometriosis, an egg has a 15% chance of being fertilized and thereupon resulting in a baby, that same egg, in a woman with endometriosis would have no more than a 5% chance. Thus, if the overall chance of a having a baby per year of actively trying is about 12% then the chance in a woman with mild endometriosis (of the same age) would probably be no more than 3-4%. This serves to explain why normally ovulating women with endometriosis and patent Fallopian tubes do not benefit significantly from intrauterine insemination, with or without the use of fertility drugs, or from surgery to remove endometriotic lesions (since many endometriotic deposits are non-pigmented, thus invisible to the naked eye and cannot be removed surgically). Only IVF improves the chance of a baby per month of trying. Simply put…if a normally ovulating woman who has mild to moderate endometriosis conceives following IUI, surgery, or the use of fertility drugs, it is probably in spite of (rather than due) to such treatment.
    • Women with long gaps between menstruation are often not ideal candidates for clomiphene: Women who consistently have >45 days between their periods will not respond well to clomiphene induction of ovulation and are better off going directly to injectable gonadotropins.
    • Multiple pregnancy: The incidence of multiple pregnancies with clomiphene induction of ovulation is about 5%. This is much lower than the 25% rate encountered when gonadotropins are given to women with absent or dysfunctional ovulation.
    Clomiphene therapy is often used as a first line approach to inducing ovulation in women with irregular or absent ovulation such as in women with polycystic ovarian syndrome (PCOS). Its use in my opinion is best confined to women who menstruate/ovulate irregularly (but who bleed at least every 45 days), younger women, women who do not have tubal disease or endometriosis, women under 40 years of age (preferably <35Y), and women who do not have DOR . It should also be avoided when there is co-existing male factor infertility. If pregnancy fails to occur after 3 consecutive cycles of clomiphene therapy, then in my opinion, it is time to move on to gonadotropin therapy, combined with IUI or IVF/ICSI depending on the underlying cause of the infertility.
    __________________________________________________________________________________________________--

    Reflecting upon the Use and Misuse of Intrauterine Insemination (IUI): Time for a Serious “Reality Check”.

    Geoffrey Sher MD

    It is hard for me to believe that more than three decades have flown by since I first introduced intrauterine insemination into the clinical arena (Journal of Fertility & Sterility, April, 1984). At that time and for more than 2 decades thereafter, I held the strong belief that IUI would provide a less expensive, safe and equally successful alternative to IVF in cases where the woman had at least one (1) patent Fallopian tube…. How wrong I was! In my defense however, let me say that in the 1980’s and 90’s the reported National IVF success rate was under 15% while y IVF success rates are now often 4 or even 5 times higher.

    Today I believe that IUI is being over-used, is not nearly as beneficial as I once thought and that there are (often ignored) serious down-sides to its use. Here is one important example: Women who fail to ovulate or ovulate dysfunctionally, often respond to controlled ovarian stimulation (COS) by the releasing (ovulating) of several eggs at a time. Since unless IVF is used, it is not possible to control/regulate the number of embryos reaching the uterus, the risk of high-order multiple pregnancies (triplets or greater) is far greater with IUI. And, multiple pregnancies (especially triplets or greater) carry a very high maternal and neonatal risk.

    Here are a few of the misperceptions about the use of IUI:

    1) IUI is a “cost saver”. However, given the fact that IVF is at least 3-4 times more likely to be successful, when one looks at cost per baby (rather than cost per procedure) this turns out to be a fallacy. But cost also comes in the form of emotional currency and this needs to be measured in terms of the much lower chance of success with IUI.
    2) "IUI is less invasive than IVF"... ....True! However aside from the surgical egg retrieval (which is a very safe procedure in the right hands/setting), IUI with gonadotropins requires largely the same drugs, preparation and monitoring as does IVF and the success rate is several fold lower than IVF.
    3) The use of oral Clomiphene Citrate for IUI- COS provides the same success rates as does Gonadotropin-IUI. This is absolutely incorrect. In fact the IUI success rate with clomiphene is about 30% lower than when gonadotropins are used.
    4) Natural cycle IUI has benefit: This is only true when frozen donor sperm is used for inseminations and in the isolated cases where there is non-immunologic cervical hostility to sperm. In all other cases, COS is needed to improve success.
    5) IUI can be used in cases of Embryo Implantation Dysfunction: Given the complexity of treatment is in cases where a thin uterine lining, significant uterine anatomical disease or immunologic implantation dysfunction (IID) prevents a healthy pregnancy, it is my opinion that IVF is the preferred primary approach.
    6) IUI can supplant or replace IVF in all cases where there is patency of at least 1 Fallopian tube. However, contrary to popular belief, there is no evidence that IUI improves pregnancy potential in cases of:
    a. Moderate or severe male factor infertility
    b. Endometriosis with patent Fallopian tubes. Since inseminating sperm does not overcome the main impediment to fertility, i.e., a "toxic" peritoneal factor that compromises sperm penetrating the egg envelopment).
    c. Older women (over 40y) where the IUI pregnancy yield is only about 2% per treatment cycle.

    Upon Honest Reflection:
    Unfortunately, too many physicians who should (and alas often do) know better, still liberally recommend IUI preferentially in cases of moderate or severe male infertility, older infertile women or those with diminished ovarian reserve (DOR), cases of endometriosis or where there is clear evidence of an anatomical r immunologic implantation issue. Such women would be much better advised to go directly to IVF but find themselves attracted to what they erroneously consider to be a much lower cost alternative.

    Then there is the fact that many infertile patients, erroneously believing that IUI is less risky that IVF, provides an equivalent chance of success, and comes at a much lower price tag, put undue pressure on their physicians to first try the former several times before resorting to the latter.

    To make matters worse, many misguided insurance providers (purely for economic reasons) demand that their female clients who have at least 1 patent Fallopian tube, first undergo several unsuccessful attempts at IUI before becoming eligible for IVF. And they often take this position regardless of cast iron indications that IVF should be the primary treatment of choice.

    In summary, it is my opinion that IUI is presently an over-prescribed treatment. As such, we as physicians need to rethink the basis upon which we recommend IUI and educate our patients appropriately

    Terry - November 11, 2018 reply

    Dear Dr. Sher,
    Thank you for your response. I have looked at your blog as well.
    – As chances are 5% for a woman aged 40 to get pregnant each cycle, is my best approach to keep trying? Do I have any recourse? If not Clomid, then what? Frankly, being a scientist myself and reviewing the literature it has me somewhat concerned, but given my fertility history not yet alarmed.
    – I have read carefully your blog on Clomid. I could not find studies demonstrating 30% less likely of pregnancy with Clomid vs natural conception. Indeed, 80% of cases in which an egg is produced, pregnancy rates seem to be similar to natural rates.
    – Since the 2017 NIH study did not correlate AMH or FSH monitoring as being correlated to pregnancy (https://www.nih.gov/news-events/news-releases/ovarian-reserve-tests-fail-predict-fertility-nih-funded-study-suggests), would you suggest ultrasound follicle counting as a rough guide to fertility?
    – NIH studies indicate a lesser conception rate with gonadotropin vs clomid (taken independently, not together) https://www.ncbi.nlm.nih.gov/pubmed/26398071

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 11, 2018 reply

    The chance of a natural pregnancy per month of trying at 40y, is about 5%. With injectable gonadotropins (with or without IUI) it is only very slightly increased and with clomiphene the chance is under 3%. The only way (in my opinion) to increase the odds is through IVF.

    Good luck!

    Geoff Sher

  • Cassie - November 10, 2018 reply

    Hi Dr. Sher i was prepping for fet with estfome tablets 3 4mg each a day a day from day 2 to 7 then 4 4mg a day 7 to 11 my lining on day 8 was 12mm so all good but had my e2 bloods and levels were only 62ng/l so my doctor decided to cancel based on low e2 but I am not sure why it matters since its medicated fet. 1 Do you thinks e2 levels are important for medicated e2,
    2 also what he would you do differently next cycle to increase your e2 to acceptable levels Thanks as always

    Cassie - November 10, 2018 reply

    It was day 11 of pills my e2 bloods were taken

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    Copy

    Geoff Sher

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    I cannot say I disagree with your RE’s decision. However, in my opinion, it is far better to prep the uterus with injectable estradiol valerate (Delestrogen) or using skin patches than adninistering estrogen it orally or vaginally.

    Geoff Sher

  • Kay - November 10, 2018 reply

    Hi Dr. Sher,
    My husband and I have had 11 failed IVF’s & 5 failed IUI’s. This has included: One with 2 donor egg embryo’s day 3, one with 2 donor egg embroyo’s day 3( new cohort) – had positive pregnancy w/ very high hcg numbers, saw heartbeat at week 6, miscarried next wk, 1 with DE day 5 blast – highest quality grading – no pregnancy. Prior to that we did transfered 3 fully donated embryo’s no dna of our own, all failed. Prior to that, when I was in my mid 30’s I had 1 natural pregnancy (never pregnant before in life) that I miscarried in first trimester for no reason. Then had 2 pregnancies in my mid 30’s from ivf that never made it to 8 weeks. So, a total of 4 failed pregnancies and many many cycles w/ no pregnancy. We are working w/ a very reputable agency yet, nobody can explain why. My husband and I have had every genetic test under the sun I think, and we have no abnormalities nor did the last one we lost. His sperm is fine. I am 46, he is 38. I am homozygous for C677T and take baby aspirin, folbic, rx prenatal and Lovenox. I’m also hypothyroid -Not Hashitmoto’s. I have no antibodies. I take Brand Synthroid ( although I much prefer Armour). I am RH- . I’m guessing there is some immune factor going on that may be why I can’t get pregnant or, I can’t carry. We are wondering if we are better off looking at adopting as we can no longer afford it and the disappointment. Or if there could still be hope? Can you kindly share your thoughts? Thank you!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
    It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
    1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
    2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
    We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
    3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
    4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
    a. A“ thin uterine lining”
    b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
    c. Immunologic implantation dysfunction (IID)
    d. Endocrine/molecular endometrial receptivity issues
    Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
    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.
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • 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
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • 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
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • 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
    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
    Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
    • Early pregnancy loss (first trimester)
    • Late pregnancy loss (after the first trimester)
    • Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
    • Early pregnancy losses usually occur sporadically (are not repetitive).
    In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
    Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
    There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
    Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
    Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
    1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
    • Inadequate thickening of the uterine lining
    • Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
    • Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
    • Deficient blood flow to the uterine lining (thin uterine lining).
    • Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
    • Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
    2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

    IMMUNOLOGIC IMPLANTATION DYSFUNCTION
    Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
    But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
    Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
    Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

    Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
    However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
    DIAGNOSING THE CAUSE OF RPL
    In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
    Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

    • Karyotyping (chromosome analysis) both prospective parents
    • Assessment of the karyotype of products of conception derived from previous miscarriage specimens
    • Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
    • Hysterosalpingogram (dye X-ray test)
    • Hysteroscopic evaluation of the uterine cavity
    • Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
    • Immunologic testing to include:
    a) Antiphospholipid antibody (APA) panel
    b) Antinuclear antibody (ANA) panel
    c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
    d) Reproductive immunophenotype
    e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
    f) Alloimmune testing of both the male and female partners
    TREATMENT OF RPL
    Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
    Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
    Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.

    Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
    Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
    The Use of IVF in the Treatment of RPL
    In the following circumstances, IVF is the preferred option:
    1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
    2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
    The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
    Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
    There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
    The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

    I strongly recommend that you visit 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
    • 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
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • 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
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • 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
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • 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

    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Ashley SE Richards - November 10, 2018 reply

    I am 28 we have our first IVF cycle in September we were on rekovelle and menopur, and cetritide maybe around day 7. Prior to starting the cycle I was on birth control, the dr said it took me a while to respond at first we stimmed 11 days. We triggered with decapeptyl and pregnyl 10000U after 11 days of stims. At retrieval we had 16 follicles resulting in 13 eggs the embryologist said that none of the eggs were mature and didn’t mature overnight in the lab. Is this common I am 28 the follicles were between 1.7-2 in size. My RE looked at me like I was an alien and said he never has seen this. our Amh is in the lower end for my age group but not excessively low I think 20 in Dec 2017. Would stiming longer to get bigger follicles help to get mature eggs. my Hcg was 75 and my doctor mentioned they wanted around 100 and said next time try a higher dose but said they didn’t think this was the cause. Is there anyway to see how much longer the eggs needed to become mature. I ovulate on my on normally we have unexplained infertility can you ovulate non mature eggs tho? We are off to see Specialist in buffalo who mentioned a moth of priming with omnitrope and lupron. And then try gonal f, letrozole, and cetritide as needed around day 6. Any suggestions on how to get more mature eggs. My dr in Toronto said this may be my eggs and something intrinsic in them that they won’t mature.

    Ashley SE Richards - November 10, 2018 reply

    My estrodiol was 9079 prior to trigger

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    Copy!

    Geoff Sher

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
    After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
    One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.
    Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).
    Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.
    The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
    The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.
    It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.
    The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those 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 in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).
    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.
    During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
    However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.
    It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.
    In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH
    It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.
    Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.
    Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here 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 “spring board effect” represents “a double edged sword” because 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 androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. 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 in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.
    Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
    The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases) can obviate this effect
    .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
    • 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.

    If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
    Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

    Geoffrey Sher MD

  • Pooja - November 10, 2018 reply

    Thankyou so much doctor for a detailed explanation about various protocols and procedures. I will have to take treatment in India and unable to travel to U.S because of financial constraints. My doctor has planned to go for a blastocyst embryo transfer for the remaining frozen embryos. Keeping fingers crossed. You are doing a wonderful job. God bless.
    Thanks & regards,
    Pooja

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 10, 2018 reply

    Good luck Pooja!

    Geoff Sher

  • Pooja - November 9, 2018 reply

    Hi Dr.Sher,
    Myself and my husband both are 35yrs of age. We have had 2 failed ivf procedures. All my reports and my husband reports are normal. Doctor says I have good ovarian reserve and no endometrial problems. They diagnosed as unexplained infertility.Had 3-8 cell grade one embryos transferred on Oct 16,2018 under laser assisted hatching, with endometrial thickness of 9mm(triple line). 2 weeks post et,beta hcg was 41mIU/ml.3rd week it was 75.6mIU/ml. After 3 days it dropped to 27mIU/ml. My doctor said it’s a failure. I have been tested for natural killer cells which was negative. Also doctor had given intra lipid iv infusion prior to et even though nk cells were negative. I am extremely disheartened.Have stored 3-8 cell grade two frozen embryos. Please suggest how do we go about a successful pregnancy.
    Thanks and regards,
    Pooja

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 9, 2018 reply

    Please note that very few laboratories in the united States can test adequately for immune factors and often do not even do the correct tests.

    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:
    o For 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).
    o For 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

    ADDENDUM:

    UWhenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
    It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
    1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
    2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
    We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
    3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
    4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
    a. A“ thin uterine lining”
    b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
    c. Immunologic implantation dysfunction (IID)
    d. Endocrine/molecular endometrial receptivity issues
    Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).

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