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Ovarian Stimulation For Women with Diminished Ovarian Reserve (DOR) and in Older Women undergoing IVF

by Dr. Geoffrey Sher on December 12, 2015

Two main factors determine the quality of a woman’s eggs at ovulation or egg retrieval.  First is her age and second is the protocol used for ovarian stimulation. With the possible the exception of cases where there is severe sperm dysfunction, it is the chromosomal integrity of the egg rather than the sperm that will ultimately determine the chromosomal integrity of the embryo (i.e. its “competency”, or its potential to propagate a healthy babies). It therefore follows that the only way by which to influence embryo “competence” is through the selection and implementation of an optimal protocol for ovarian stimulation. Since older women (≥35 years) and those who have diminished ovarian reserve (DOR) are at greatest risk of yielding “incompetent” eggs, they are the ones that require special attention. This article will highlight the reasons why such women are the ones most prone to produce poor quality eggs and embryos and how best to address ovarian stimulation in an attempt to minimize this risk.

Cells that have a full chromosomal component are termed euploid while those that do not, are aneuploid. Most euploid eggs arecompetent”, that is, they are the one’s that are most likely to propagate euploid, “competent” embryos. Aneuploid, “incompetent” eggs will invariably develop into aneuploid, “incompetent” embryos. There is a progressive increase in the incidence in egg/embryo aneuploidy with advancing age. To put numbers to the equation; by time a woman reaches 35 yrs; approximately 60% of her eggs are likely to be aneuploid. By the time she reaches her mid 40’s the incidence will be greater than 85%.

For example, a woman of 43 years would be fortunate if  six (6) or eight (8), of her eggs would upon being fertilized, result in one (1) “competent” embryo. As the woman gets older, the inevitable decline in egg/embryo quality results in her having a reduced ability to conceive naturally, a declining IVF success rates, an increase in miscarriages, and a rising incidence of having her baby affected by chromosomal birth defects such as Trisomy 21 (Down’s syndrome). This is why for such a woman, the anticipated IVF birth rate per egg retrieval is less than 10% (i.e. >70% lower than at age 35), the miscarriage rate increases from about 15% at 35y to >40% at age above 40y.and why her risk of having a baby with Down’s syndrome is about 0 2% at 35y as compared to 2% at 44y).

The anticipation of poor IVF outcome statistics for women in their mid-40’s makes IVF with ovum donation the most rational approach. Yet, in spite of this, many older women still elect to use their own eggs as long as there is even the slightest chance of having their own genetic offspring.

As a woman approaches and then engages her 40’s, her ability to produce “competent” eggs progressively declines. At the same time she experiences diminishing ovarian reserve that results in a progressive fall-off in the number of eggs she is likely to produce at egg retrieval. As a result, there will be a commensurate drop of in the number of “competent” embryos available for transfer to her uterus.

The following IVF stimulation protocols are the ones most commonly used for COS in older women and those with DOR:

1.GnRHa Flare (“Short”) protocol: Some IVF physicians advocate the use of gonadotropin releasing hormone-agonist (GnRHa)- flare protocols in which the administration of GnRHa (e.g. Lupron, Buserelin, Nafarelin, Synarel) therapy begins at the same time that ovarian stimulation with gonadotropins is started (usually with the onset of menstruation). The proposed benefit of such an approach is that the GnRHa will cause the woman’s pituitary gland to release large amounts of follicle stimulating hormone (FSH), which would augment the administered dosage of FSH and thereby synergizing the growth of ovarian follicles.

The problem associated with this “flare” approach is that concurrent with the GnRHa-induced FSH luteinizing hormone (LH) also surges. In older women and those who have diminished ovarian reserve, the out-pouring of LH can cause the ovarian connective tissue (stroma or theca) which produces excessive male hormones (predominantly, testosterone). While some testosterone is essential for optimal follicle growth, too much testosterone can compromise its development as well as egg/embryo quality. Since older women and women with diminished ovarian reserve often have increased LH production as well as an overgrown of ovarian stroma/theca (i.e. hyperthecosis), a further GnRHa-induced increase in LH can so elevate local ovarian testosterone levels as to severely compromise egg/ embryo “competency”.

2. Combined Clomiphene or Letrazole) /Gonadotropin Stimulation: This approach when used in older women and women with diminished ovarian reserve is also potentially harmful to egg/embryo quality. The reason is that like GnRHa, clomiphene and Letrazole also cause LH to be released in large amounts. Since these medications are given at the start of ovarian stimulation they, as with “flare protocols” can elicit ovarian over-production of testosterone. As such this approach is in my opinion far less than ideal for older women and women who have diminished ovarian reserve.

3. Mid-follicular GnRH-antagonist protocol: With this approach, stimulation with gonadotropins is commenced with the onset of the cycle. Then, several days later, once the majority of follicles have reached about 12mm in size, GnRH antagonist (e.g. Ganirelix, Cetrotide, Cetrorelix, and Orgalutron) is added. The intent in adding the antagonist is to abruptly block pituitary LH release and so prevent a “premature LH surge” with its effect of causing increased ovarian testosterone and impaired follicle and egg development.

The problem with such a regime is that women with diminished ovarian reserve already have too much of their own LH around at the beginning of the cycle. Accordingly, blocking LH release only 6-7 days into the stimulation does nothing to prevent the early adverse effects of too much LH-induced ovarian testosterone on early egg/embryo development. It should be borne in mind that eggs are often at their most vulnerable, early on in the cycle. Thus, in my opinion such protocols are also less than optimal for older women and for those with diminished ovarian reserve.

4. GnRHa (“Long”) Pituitary down-Regulation Protocol:

  1. The “Standard” Long Protocol Approach: This protocol, which is the mainstay of ovarian stimulation for IVF, is either initiated about 1 week after natural ovulation (a “luteal phase start”) or is launched off a monophasic birth control pill (a “BCP start”). In the case of the latter, the BCP is taken for at least 8 days before, GnRHa (e.g. Lupron/Superfact/Buserelin) is added daily. Two days after starting the GnRHa, the BCP is stopped. Menstruation usually ensues within 3-5 days. GnRHa administration is continued and gonadotropin (Follistim/Gonal-F/Puregon, Bravelle, and Menopur) stimulation is initiated. Both daily Gonadotropin stimulation and GnRHa are continued until the day of the “hCG trigger”.

The initial administration of agonist serves to rapidly expunge pituitary FSH and LH causing an immediate rise in the blood levels of both hormones. Then, within a few days, having virtually exhausted/depleted pituitary gonadotropin stores, the blood levels of FSH and LH both rapidly decline, such that by the time menstruation occurs, the levels are very low. The initial premenstrual GnRHa-induced rise in FSH helps recruit ovarian antral follicles for the upcoming cycle, while the ultimate virtual depletion of LH serves to prevent excessive ovarian testosterone production and protects egg quality.

I prefer to use pure FSHr (Folistim, Puregon, Gonal F) for ovarian stimulation for IVF with the initial dosage being reduced by about 25% within a few days.  Thereupon 75U Menopur is added daily, up until the hCG trigger.

  1. Modified Long Protocols:
      1. Agonist/Antagonist Conversion protocol (A/ACP): Agonists might competitively inhibit follicle response to FSH. Therefore, in an attempt to improve follicle response to FSH we modified the “standard approach” (a- above) as follows: Rather than continuing to give GnRHa throughout the stimulation protocol, we here supplant GnRHa with low dosage GnRH antagonist starting with the initiation of menstruation, continuing throughout stimulation until the day of the “hCG trigger” at which point both the antagonist and gonadotropins are discontinued. We have had very good results using the A/ACP modification of the “standard long pituitary down-regulation protocol”. In fact it has become my preferred approach for most women with a normal ovarian reserve, who undergo ovarian stimulation for IVF.
      1. Agonist/Antagonist Conversion Protocol (A/ACP) +“Estrogen Priming” (LA10-E2V): Estrogen primes follicle FSH receptors, thereby enhancing response to FSH. This forms the basis of the “estrogen priming” approach in women with diminished ovarian response. The approach involves administering estradiol by daily injection, or by skin patch starting about 10 days prior to initiating high dosage gonadotropin stimulation. As with the standard A/ACP, the estrogen priming protocol is initiated a week post-ovulation (luteal phase start) or is launched off a birth control pill regime of at least 10 days. It also starts with GnRHa administration for about 5 days whereupon menstruation ensues and the agonist is supplanted by an antagonist. But this is where things change slightly such that instead of directly initiating  FSHr (Follistim/Gonal-F/Puregon)  injections, the patient, while continuing to take the GnRH antagonist now receives twice weekly estradiol valerate injections or daily estradiol skin patches (I prefer the former) for a period of about 10 days. Thereupon, daily high dosage FSHr (750U) is administered once daily. Four to five days later, 75U Menopur daily is added. “Estrogen priming” is continued until more than 50% of the follicles are at least 12mm in size whereupon it is discontinued.
  1. Mini-IVF or Natural Cycle IVF for women with DOR? It is quite understandable that many women with DOR are easily persuaded that less (or no) ovarian stimulation offers a more “natural” and less “stressful” approach on eggs than a robust, high gonadotropin-based, long-pituitary down regulation approach. This, in my opinion is a fallacy and can compromise rather than benefit IVF outcome in such cases. Even in young women in their early or mid-30’s, the IVF success rate per fresh “natural” or “mini”  IVF cycle is much lower (<15%)  than that which can be achieved through the use of conventional long down-regulation protocols, where the anticipated success is at least double this rate (30%). Mini-IVF is usually conducted using clomiphene or Femara, alone or in combination with Menopur, all of which is associated with the production of excessive LH-induced ovarian testosterone. Furthermore, low dosage stimulation will result in fewer eggs being available, thus further reducing the odds of IVF success per egg retrieval conducted. Natural cycle IVF is in my opinion also not in the best interest of women with DOR, because with such an approach, nothing is done to control the exaggerated production of LH by the woman’s own pituitary gland.

Addendum:

Human Growth Hormone (HGH) Supplementation. Recently, I began selectively adding human growth hormone (HGH) supplementation to simulation protocols in women with DOR, in cases where there is a history of the woman repeatedly producing poor quality eggs and in older women (>38Y) undergoing IVF. There is evidence that this might enhance mitochondrial activity and thus improve egg maturational division (meiosis).

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  • Suzanne moore - October 16, 2017 reply

    Dear Geoffrey
    Please would you advise in your opinion the best protocol for me:
    I have 2 healthy sons with IVF both using the puregon then orgalutran protocol. I had 14 then 10 follicles with these cycles. Husbandssperm count is excellent
    This was 3-6 years ago. Now I am 38. My amh is 12, my fsh is 8 and AFC around 10.
    This year I have had 2 failed IVF cycles first was agonist cycle(I think it’s called that?) Lupron then menopur: 5 follicles. 2 low quality replaced. No pregnancy.
    This cycle was estrogen primed micro dose flare with pergoveris 300mcg daily: so far this shows poor response with only 4 follicles of 14mm on day 10… cycle will likely be canceled.
    My question is which protocol would you recommend? Why could I not try puregon protocol again? I realize I’m getting older but the drop in follicle development seems so substantial that I think Im on the wrong protocol….please help I’m confused
    Thank you very much
    Suzanne

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 16, 2017 reply

    Here is the protocol I advise for women, <40Y 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 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

  • Maria - October 7, 2016 reply

    Hi Dr. Sher,
    I read your book and wish I would have 3 years ago. My husband had a successful vasectomy reversal but two years later, no pregnancy and RE found his sperm has 90% antibodies. My first urologist recommended we go for TESA and IVF (instead of vasectomy reversal) and we should have listened! I am 36, AMH of 0.85, FSH of 5, Day 5 antral follicle count of 4. So it seems we have less eggs to work with but I’m hoping the quality will be ok. I’m going in for my first IVF and RE has recommended short antagonist for me. So Puregon of 225 starting day two and Orgalutran starting day 7. What do you think of this first attempt protocol for me?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - October 7, 2016 reply

    It sounds as if you have diminished ovarian reserve (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
    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

  • Iveta Scott - May 30, 2016 reply

    Hello, Dr Sher. Can, in your opinion, administration of the Cabergoline counteract harmful to the egg quality hyper production of LH in mini IVF cycles?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - May 31, 2016 reply

    No I do not think this swill happen.

    Geoff Sher

  • Nicola - December 30, 2015 reply

    What would be the best protocol for someone with pcos, aged 39?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 30, 2015 reply

    Hi Nicola,

    That is a loaded question which I can only answer once I have access to a great deal more information. If you read the articles below, you will see what I mean and gain much more insight into what would be needed to answer your question authoritatively.

    S…please access my new pnew blog. When you get to the “home page” of the Blog on this website, find the “search bar” and type in any of the articles below by title, “click” and you will immediately be taken to these.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF: Comparing “conventional” use of GnRH antagonists to the
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Measuring and Interpreting Blood hCG to Assess Pregnancy Viability Following ART Treatments.
    • Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
    • Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
    I invite you to call 702-699-7437 or 800-780-7437 and set up a one hour Skype consultation with me to discuss your case in detail.

    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.

    Happy New Year!

    Geoff Sher

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