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The Importance of Individualizing Ovarian Stimulation Protocols in IVF “Poor responders” and “High Responders”

by Dr. Geoffrey Sher on July 23, 2017

Indiscriminate selection and use of protocols of Controlled Ovarian Stimulation (COS) can be decidedly detrimental to egg and embryo competency/quality especially when it comes to IVF conducted in women on opposite sides of the spectrum of response to fertility drugs …i.e. ” high responders and “low responders. It is in such cases that protocols must be individualized.

“High responders” tend to have increased ovarian reserve (high blood levels of AMH) and produce large numbers of ovarian follicles as well as eggs while “low responders’” have tend to have low AMH levels (diminished ovarian reserve-DOR) and produce few follicles/eggs. High responders have a tendency to over-stimulate in response to even modest gonadotropin stimulation and as such are often at risk of developing a life-endangering condition known a severe ovarian hyperstimulation syndrome (OHSS)… while poor responders produce few follicles (even in response to high dosage COS protocols) and as such are clearly not at risk of developing OHSS, regardless of the ovarian COS protocol prescribed (see elsewhere on this blog).

High and poor responders have one characteristic in common, namely that in both cases, there is an increased tendency for their eggs to be chromosomally abnormal (aneuploid /”incompetent”) that are incapable of propagating viable pregnancies (i.e. “incompetent”). Thus in both cases egg quality is often compromised, thereby adversely impacting embryo “competency” and IVF outcome.

Many high responders, especially those who have a condition known as polycystic ovarian syndrome (PCOS) have overgrowth of ovarian connective tissue known as stroma or theca (ovarian stromal hyperplasia or hyperthecosis). This is due to inherent over-activity of pituitary Luteinizing Hormone (LH). With PCOS, the ovarian stroma often over-produces he stroma produces male hormones (mainly testosterone) which upon reaching the follicles in excess, has a damaging effect on egg development. While a small amount of testosterone is essential to orderly follicle and egg development and estrogen production, excessive ovarian testosterone compromises both follicle and egg development. Such eggs will, upon the subsequent administration of hCG (intended to “trigger” reproductive, maturational division or meiosis” to promote orderly separation of egg chromosomes in preparation for egg maturation) will be more likely to end up having an irregular quota of chromosomes (aneuploidy). Aneuploid eggs will upon fertilization, inevitably propagate aneuploid embryos that will either fail to implant in the uterine lining (endometrium) or will spontaneously be lost as a “chemical pregnancy or an early miscarriage.

Unlike high responders who have a tendency to over-produce follicles and eggs, poor responders fail to produce an adequate number of follicles even when an aggressive high-dosage protocol of ovarian stimulation is used. In spite of this major difference, the two conditions have one thing in common namely that they are both associated with high pituitary LH activity, ovarian stromal hyperplasia (or hyperthecosis), increased ovarian testosterone and the fact that an inordinately high percentage of eggs produces turn out to be aneuploid.

Since both many high and poor responders often have increased LH-induced ovarian testosterone production, they both require pituitary down-regulation with an agonist in advance of initiating ovarian stimulation. To do this requires pituitary down regulation with a birth control pill (for a few weeks) prior to COS, followed by the administration of an agonist such as Lupron/Buserelin/Superfact/aminopeptidyl a few days before initiating COS (gonadotropin stimulation). Poor responders often do better with a modification of this approach the agonist/antagonist conversion protocol –A/ACP and in some cases the addition of estrogen “priming and human grow the hormone (hGH). High-responders require low dosage COS with gonadotropins while poor responders require higher dosage protocols.
As stated, poor responders with DOR and high responders with PCOS often both manifest with exaggerated ovarian LH bioactivity and it is thus this group of patients where special attention needs to be given to selecting an optimal ovarian stimulation protocol that would minimize the effects of exaggerated ovarian LH-induced egg/embryo damage.

Eggs are recruited genetically for a given cycle, 3-4 months before the cycle in which they are to use. There is absolutely nothing we can do to influence the egg recruitment process or their development during their 3-4 month journey. No nutritional supplements or treatments will help improve their quality. All that we can do is protect their development (oogenesis) during COS by individualizing/ (customizing) the protocol of ovarian stimulation in such a way as to control/regulate LH-induced ovarian male hormone (mainly testosterone) production. This, in my opinion, requires:
1. Prior pituitary LH down-regulation using agonists (Lupron/Buserelin/Superfact/Aminopeptidyl) starting 5-10 days prior to initiating ovarian stimulation.
2. Avoiding “flare protocols” (where agonists are 1st administered with the onset of gonadotropin administration (i.e. without prior LH-down-regulation) that causes increased pituitary release of LH at the very time that ovarian stimulation with gonadotropins commences.
3. Limiting the use of menotropins such as Menopur, (gonadotropins such as Menopur) that contain LH/hCG
4. Avoiding supplementing early ovarian stimulation with hCG (which similar to LH, augments pituitary LH release) or testosterone
5. Limiting admistration of clomiphene and Letrozole for ovarian stimulation which promote the release of additional pituitary LH. This is especially applies to women with DOR.

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  • C - January 21, 2018 reply

    Hi Dr Sher,
    I did Ivf 3 years ago when I was 33 for severe male factor (zero motility and low morphology and count) that resulted in my daughter being born. We did a protocol of birth control with mild stimulation using puregon as my amh was 6.8 ng/ml and they worried I would over stim. We used orgalutron to suppress ovulation and hug trigger. My fsh at time was 3.5 iu/l. We only retrieved six eggs, all fertilized and got 2 normal CFCs tested blasts. One was my daughter. The second was used as a fet when I was 35 but did not implant I believe because I had the noro virus flu at the time. Did another egg collection again with birth control then again with puregon and orgalutron but also with menopur and much higher doses 225 of each daily. Only five eggs collected, all fertilized, 3 made it to blast, all abnormal. Did another round this time using luprints flare protocol. Estrogen priming ( no birth control) lupron flare, then lupron, menopur and puregon daily at max doses. Also with growth hormone added. Retrieved ten eggs and only five fertized and all then made it to blast. Only one normal after testing. It did not implant. Also had era testing to check if lining was receptive and how many days of progesterone was needed before implantation. I always have done natural cycles as do not respond to taking estrogen to thicken lining. My lining never really got above 7. My question is do you think it is worth trying again? Do you think it is a implantation issue or a problem with the protocol? I just turned 36 this year. Thank you for the advice.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - January 21, 2018 reply

    In my opinion, a lining of <8mm will very rarely sustain an adequate implantation.

    It was as far back as 1989, when I first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the subsequent successful implantation of embryos in IVF patients. This study revealed that when the uterine lining measured <8mm in thickness by the day of the “hCG trigger” (in fresh IVF cycles), or at the time of initiating progesterone therapy (in embryo recipient cycles, e.g. frozen embryo transfers-FET, egg donation-IVF etc.) , pregnancy and birth rates were substantially improved. Currently, it is my opinion, that an ideal estrogen-promoted endometrial lining should ideally measure at least 9mm in thickness and that an endometrial lining measuring 8-9mm is “intermediate”. An estrogenic lining of <8mm is in most cases unlikely to yield a viable pregnancy.

    A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) ) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation in the event that no pregnancy occurs.

    The main causes of a “poor” uterine lining are:

    1. Damage to the basal endometrium as a result of:
    a. Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth
    b. Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
    2. Insensitivity of the basal endometrium to estrogen due to:
    a. Prolonged , over-use/misuse of clomiphene citrate
    b. Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
    3. Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity.. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect can be further exaggerated when certain methods for ovarian stimulation such as agonist (Lupron/Buserelin) “flare” protocols and high dosages of menotropins such as Menopur are used in such cases.
    4. Reduced blood flow to the basal endometrium:
    Examples include;
    a. Multiple uterine fibroids - especially when these are present under the endometrium (submucosal)
    b. Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

    “The Viagra Connection”

    Eighteen years ago years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for to women who had implantation dysfunction due to thin endometrial linings I was proud to announce the birth of the world’s first “Viagra baby.” Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported treated and many have gone on to have babies after repeated prior IVF failure.

    For those of you who aren’t familiar with the use of Viagra in IVF, allow me to provide some context. It was in the 90’s that Sildenafil (brand named Viagra) started gaining popularity as a treatment for erectile dysfunction. The mechanism by which it acted was through increasing penile blood flow through increasing nitric oxide activity. This prompted me to investigate whether Viagra administered vaginally, might similarly improve uterine blood flow and in the process cause more estrogen to be delivered to the basal endometrium and thereby increase endometrial thickening. We found that when Viagra was administered vaginally it did just that! However oral administration was without any significant benefit in this regard. We enlisted the services of a compound pharmacy to produce vaginal Viagra suppositories. Initially, four (4) women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

    Our findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that was followed by enhanced endometrial development in all four cases. Three (3) of the four women subsequently conceived. I expanded the trial in 2002 and became the first to report on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness. Forty five percent (45%) achieved live births following a single cycle of IVF treatment with Viagra The miscarriage rate was 9%. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.

    Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects

    It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about 30%-40% of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

    Combining vaginal Viagra Therapy with oral Terbutaline;
    In my practice I sometimes recommend combining Viagra administration with 5mg of oral terbutaline. The Viagra relaxes the muscle walls of uterine spiral arteries that feed the basal (germinal) layer of the endometrium while Terbutaline, relaxes the uterine muscle through which these spiral arteries pass. The combination of these two medications interacts synergistically to maximally enhance blood flow through the uterus, thereby improving estrogen delivery to the endometrial lining. The only drawback in using Terbutaline is that some women experience agitation, tremors and palpitations. In such cases the terbutaline should be discontinued. Terbutaline should also not be used women who have cardiac disease or in those who have an irregular heartbeat.
    About 75% of women with thin uterine linings see a positive response to treatment within 2-3 days. The ones that do not respond well to this treatment are those who have severely damaged inner (basal/germinal) endometrial linings, such that no improvement in uterine blood flow can coax an improved response. Such cases are most commonly the result of prior pregnancy-related endometrial inflammation (endometritis) that sometimes occurs post abortally or following infected vaginal and/or cesarean delivery.
    Viagra therapy has proven to be a god send to thousands of woman who because of a thin uterine lining would otherwise never have been able to successfully complete the journey “from infertility to family”.

    To be effective, Viagra must be administered vaginally. It is NOT effective when taken orally. We prescribe 20mg vaginal suppositories to be inserted four times per day. Treatment is commenced soon after menstruation ceases and is continued until the day of the “hCG trigger.” While ideally the treatment should be sustained throughout the first half of the cycle, most women will respond within 48-72 hours. For this reason, Viagra can be used to “rescue” a poor lining after the cycle has already started, provided that there is enough time remaining prior to ovulation, egg retrieval or progesterone administration.

    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 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 .

    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


    Christy - January 21, 2018 reply

    Thank you for the quick reply and suggestions to increase lining thickness. If I were to do another round of Ivf do you think I should use the same microdose flare protocol or would you consider me a poor responder. Should I also avoid menopur? Thanks, Christy

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - January 22, 2018 reply

    Hi Christy!

    You are most welcome.

    Christy, I do not advocate the use of “flare protocols” and I advise against >75U Menopur daily…especially in “poor responders” who have DOR.“ Flare protocols” involve 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.

    Geoff Sher

  • nina - October 31, 2017 reply

    I did IVF due to male infertility (husband) and have a 5 and 3 year old. I went through OHSS from retrieval (they took 31 eggs from me) and I am now overly concerned about ovarian cancer. Is this concern grounded or unfounded?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 31, 2017 reply

    Not grounded!

    Geoff Sher

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