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Optimizing Response to Ovarian Stimulation in Women Who Have Compromised Ovarian Reserve: A Personal Approach.

by Dr. Geoffrey Sher on July 8, 2016

Older women, and those who have diminished ovarian reserve (DOR) with resistance to ovarian stimulation (“poor responders” are often labeled as being producers of “poor quality” eggs and embryos, and advised to seek IVF with egg donation. In fact, in my opinion such “recipe” or “one size fits all” attitude towards ovarian stimulation is not always justified. In my opinion it should be replaced by a customized approach that addresses specific individualized needs on a case by case basis. This article addresses my personal preference in selecting a stimulation protocol in such cases.

The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically “incompetent” (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those 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 age-related effect on the woman’s “biological clock,” certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron– “flare” protocols, clomiphene and Letrozole), can 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 older women and those 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).

  • The Agonist/Antagonist Conversion Protocol Women who have a tendency to overproduce LH (i.e poor responders, older women) require a form of pituitary blockade (with GnRH agonist or an antagonist) throughout the stimulation period to prevent the progressive and excessive rise in LH –induced ovarian male hormones, (mainly testosterone) can adversely influence egg development, resulting in compromised embryo quality. However, prolonged administration of GnRH agonists (e.g. Lupron/Lucrin/Buserelin/Superfact/Decapeptyl) starting several days prior to the initiation of gonadotropin therapy (the long protocol) and then continued through the gonadotropin stimulation phase (until the day of the hCG trigger) has one possible down side, namely that the agonist can compete for FSH binding sites on follicle cell FSH receptors and thereby blunt the response to gonadotropin stimulation. Obviously this is the last thing that women who have DOR (“poor responders”) need. It is for this reason that I, some time back developed the Agonist/Antagonist Conversion Protocol (A/ACP) With this protocol, the women starts by taking a combined BCP for 8 or more days, whereupon a GnRH agonist is overlapped with the pill for two days. The BCP is then stopped and daily agonist administration continues until the onset of menstruation (usually within 3-6 days). At this point the agonist is completely supplanted with daily injections of 125mcg, antagonist (Ganirelix/Cetrotide/Orgalutron). Commencing within a few days of initiating antagonist therapy, daily FSH-gonadotropins (usually Folistim) injections are commenced. A few days later daily injections of Menopur 75U daily is added. Gonadotropin and antagonist therapy are both discontinued on the day of the hCG trigger
  • Agonist/antagonist conversion protocol combinred with Estrogen “priming”: The addition of parenteral estradiol valerate (E2V) for about a week following the initiation of the agonist/antagonist conversion protocol (A/ACP), prior to commencing FSH-dominant gonadotropin stimulation appears to further enhance ovarian response, presumably by up-regulating ovarian FSH-receptors. Accordingly, for women with severely diminished ovarian reserve (“very poor responders”) he adds “estrogen priming” by administering of estradiol valerate (Delestrogen) during the 1st week of antagonist therapy. This appears to enhance ovarian follicular response to gonadotropins. Following one week of “estrogen priming”, gonadotropin therapy is commenced and is this is continued along with antagonist therapy (as above) until the day of the hCG trigger. In my opinion, in cases of severe DOR with very poor response to stimulation, the use of A/ACP + “estrogen priming ” there is in my experience a relatively low (<15%) cycle cancellation rate. In fact , a significant number of patients who previously had been advised to give up and switch to egg donation subsequently achieved viable pregnancies using the A/ACP with “estrogen priming”.
  • Augmentation of ovarian stimulation with Human Growth Hormone (HGH) Several researchers have shown that the administration of human growth hormone (HGH), as an adjunct to ovarian stimulation, enhances follicle response in older women and those with DOR and so can help optimize egg quality. It is thought that HGH hormone by increasing the production of insulin-like growth factor 1 (IGF-1), improves follicle development, estrogen hormone production and egg maturation. Two basic mechanisms have been proposed: 1) improving the response to gonadotropin therapy by up-regulating the FSH receptors on the granulosa cells that form the inner lining of follicles and, 2) through a direct enhancing effect of HGH on the egg’s mitochondrial activity.  While human eggs do have HGH receptors, those retrieved from older women show decreased expression of such receptors (as well as a reduction in the number of functional mitochondria) as compared with those derived from younger women. In fact, it has recently been shown that older women treated with HGH showed a marked increase in functional mitochondria in their eggs along with improved egg quality. My personal experience in selectively prescribing HGH as an adjuvant to women with DOR, older women and those with unexplained egg quality deficits, is that if used in combination with the A/ACP it seems to indeed enhance egg quality and ovarian response, culminating in improved IVF outcome.
  • Embryo Banking: 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 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

“When designing an individualized ovarian stimulation protocol woman with diminished ovarian reserve and/or older women the primary objective is to optimally regulate the intraovarian testosterone environment by: 1. avoiding protocols of stimulation that cause increased LH exposure, using predominantly FSH-dominant medications such as Follistim/Gonal-F and Puregon, limiting the administration of LH-containing gonadotropins, augmenting the protocol by adding HGH accurately timing the hCG trigger to coincide wit optimal follicle/egg development and offering such women access to “Embryo Banking with the selective transfer of PGS-selected embryos.

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  • famous gynecologist in hyderabad - February 22, 2017 reply

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    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 22, 2017 reply

    Thank you kindly!

    Geoff Sher

  • Melissa - October 4, 2016 reply

    Hi, I had two canceled IVF cycles due to poor response to stimulation meds. I have DIminished Ovarian Reserve, stage 4 endimitriosis that I had robotic surgery on. The doctor changed my protocol to a mini IVF cycle were I did much better. They were able to retrieve 3 eggs all fertilized & made it to day 6. They were frozen & PGS was done. All 3 came back abnormal. Do I still have a chance if I continue to do IVF? I just turned 40. I became pregnant naturally 2 years ago but we lost our son at 22 weeks. He was healthy as was the placenta. I went into early labor & they believe it was a placenta obruption. I had a fibroid growing with my son. After this loss I opted to have the fibroid removed with robotic surgery & this is when they found stage 4 endomoitriosis. Do I have a chance of becoming pregnant again with my own eggs?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 4, 2016 reply

    Your ability to have an IVF baby, will very much depend on 2 things. the one is whether due to your endometriosis you have an associated implantation dysfunction and the other is your diminished ovarian reserve (DOR) and how this would affect ovarian stimulation.

    1. Endometriosis and implantation:

    More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

    Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

    The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
    The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that in cases where the condition is further compromised by an IID associated with NKa and/or for older women(over 35y) who have diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

    2. DOR:

    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•
    . 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!

    I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

    Email: Julied@sherivf.com

    OR

    Phone: 702-533-2691
    800-780-7437

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

  • Mamata Deenadayal - August 21, 2016 reply

    i am a practising gynecologist in india would love to have the details of this very impressive concept
    can oral estrogens be used instead of parentral as delestrogen is not available in india
    dose of growth hormone used
    would be happy to share my results
    regars

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 21, 2016 reply

    Feel free tom call Tina at 702-892-9696 and set up a time when we could talk over the phone.

    Thanks!

    Geoff Sher

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