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IVF Outcome: How Age, Ovarian Reserve and the Protocol Used for Controlled Ovarian Stimulation (COS) Influences Success

by Dr. Geoffrey Sher on January 3, 2016

It is the egg’s numerical chromosomal integrity (ploidy) that is the most influential in influencing its subsequent ability post-fertilization, to propagate a “competent” embryo (one that has 46 chromosomes and is capable of developing into a healthy pregnancy). And it is the ploidy of the embryo that determines reproductive success. Thus, egg ploidy is the rate-limiting factor in human reproduction.

 

Ovarian reserve refers to the number of eggs remaining in the ovaries. An AMH of <2.0ng/ml or >15pmol/L, (measured any time in the cycle) and a basal (day 2,3 or 4) FSH of >9.0MIU/ml is indicative of diminishing or diminished ovarian reserve (DOR) and suggests that that a reduced number of eggs are likely to be retrieved following ovarian stimulation.

 

Ovarian reserve itself is not a measure of egg quality but it is the woman’s age that is the main determinant of egg competency/ploidy. To put matters in perspective and by way of example, at age 30Y, about 50% of eggs have a normal number of chromosomes (euploid). At 40y it declines to about 20% and at 45y …to less than 10%. The remaining eggs will have an irregular number of chromosomes (aneuploid) and thus will invariably propagate incompetent (aneuploid) embryos which will either not implant, result in a chromosomal miscarriage or propagate chromosomal birth defects such as Down syndrome.

 

Aside from a woman’s age, it is the protocol used for ovarian stimulation, which by establishing the environment in which eggs develop during ovarian stimulation. An adverse environment will result in a greater percentage of eggs being aneuploid. The likelihood of such an adverse effect increases with diminishing ovarian reserve. This is why it is so important to individualize the protocol used for ovarian stimulation, most particularly when it comes to older women and those who have DOR.

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  • Sneha Pandit - September 28, 2018 reply

    Hi Dr Sher, I am 31 years old, low AMH : 0.5 and high FSH : 14 with diminished ovarian reserve. I started my first IVF cycle in India. They started me on 300iu menopur on day CD2. On baseline scan I had 3-4 follicles, by day 4, there were only 2 follicles growing. They increased my menopur to 525iu. However by day 9, I only have 1 follicle growing, that too has “slow” growth. My RE is telling me that slow growth indicates poor egg quality as well. So I started mentally preparing myself for donor eggs, however your articles and comments have given me hope that I have age on my side and should still try a few more rounds with my own eggs. What would be a good protocol for DOR and poor responder to Menopur? Thanks a lot in advance.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - September 28, 2018 reply

    Women who (regardless of age) have diminished ovarian reserve (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, www. SherIVF.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
    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.

  • Elizabeth - April 1, 2016 reply

    Hi Dr. Sher. I’m 44 yrs and married with no children but trying to do all we can to get pregnant with my own eggs. Fertility tests done on my hubby turned out good. Sometime back i had an ectopic pregnancy. My right tube and ovary are normal and healthy. Recently, i underwent a laparoscopy and had my left tube removed due to Tubo Ovarian mass. As of 19th February 2016 my AMH levels were very low 0.01, FSH levels 44.81mIU/ml , LH levels 24.7mIU/ml and Prolactin level 7.8ng/ml. The TVS Pelvic ultrasound scan report shows Anteverted uterus measures 8.3*4.0*4.8cm. No evidence of any diffuse or local myometrial lesion is seen. Endometrial thickness is 6.0mm and well delineated. Right ovary measures 2.8*1.9cm and shows 12.0mm largest follicle. Left ovary is ill defined and measures 2.6*1.4cm and shows 13.0mm largest follicle. A 23*22mm TO mass is seen. Pelvic congestion is noted. Mild free fluid is seen in pelvis. I was given fertility supplements like conceva, ovares plus and ovacare for 3 months. My menses are regular (28 days) bleed for 5 days, no hot flashes, no sleepless nights nor mood swings. I have also healed very quickly. I want to begin using hgh….in what doses and on which exact dates do you recommend best for me? Also, are there other combination of fertility drugs i can use before IVF? Thank you & Kind regards.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 1, 2016 reply

    In truth, you have probably got very severely diminished ovarian reserve and need an egg donor. I do suggest that you have your AMH measured to confirm this (it can be done any day in the cycle). Age and DOR combined such as in your case, auger poorly for successful IVF. I would not refuse to treat you but I would need you to know that the chances using own eggs are very poor. If we did go ahead with your eggs, you would in my opinion need a modified, robust, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts.

    Please visit my new Blog at o to http://goo.gl/4hvjoP , 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
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • 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.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • 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?
    • 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 Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Why did my IVF Fail
    • 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
    . IVF with egg donation

    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site 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.

    Geoff Sher
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site 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.

    Geoff Sher

  • Whitney - March 26, 2016 reply

    Thank you so much for the time and energy you direct into answering questions and running this blog! I am curious of what feedback you would suggest. I am 29, with a history of mild Endometriosis and once we started going to an RE, discovered my prolactin levels were slightly elevated, but are now stabilized with medication. We went through 7 IUI’s on Clomid and then Femara with no success. We just had our first IVF cycle with ICSI, which failed. I am not sure of my AMH and FSH numbers, I only know they were normal levels for my age, and my AMH suggested I was far from DOR. I was placed on oral contraceptives and then a lupron protocol with Gonal-F and Menopur. They retrieved 39 eggs, of which 20 were mature. Day 3, 12 were still going but all at a grade 2-3. Early transfer on day 4 with two grade 2.5 embryos. None of them made it to a blastocyst. During our follow up, the RE seemed defeated and suggested we go with donor eggs. He did imply that it could be the protocol and said that although i do not encompass the symptoms of pcos, my ovaries were polycystic and perhaps that is why my egg quality was poor.
    He suggested Metformin or Anastozole (sp?) with a protocol on Ganirelix. While the two embryos that were transferred reportedly did not exhibit this, my RE said that our embryos had three pronuclei and a larger than normal polar body, and that he had only seen this a couple times in his 20 years of practice. It was a bit of shock to hear donor eggs after our first try and the attitude of our RE.
    I reached out to the embryologist later in the week though and he was not as gloomy about it, so I’m a little conflicted on the severity of our issue. He confirmed my internet searches for its term, tripolar mitosis, but encouraged me to not focus so much on that. What protocol would you suggest? I am starting to cut down my carbs and sugar intake, because I do believe I am insulin resistant, and looking into supplements to consider during our 6 month break. Thank you for your time!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 26, 2016 reply

    In cases like yours, the most likely explanation lies with the protocol used for ovarian stimulation and here there are several things to look for:

    1. The exact protocol used for ovarian stimulation:You said you were launched off a BCP and then received Lupron, but did the Dr overlap the BCP with Lupron in the last few days ofusing it (Long Protocol) or did he/she 1st wait for the period to begin before starting the Lupron (short -“Flare” protocol). The former is preferable by far…in my opinion.

    2. What dosage of Follistim/Gonal-F and Menopur was used.

    2. How long you were stimulated for because with so many follicles and the presumed fear of your developing Severe Ovarian Hyperstimulation syndrome (OHSS), I am concerned that you might have been “triggered too soon” thus prejudicing egg quality (regardless of maturation).

    3. Did you undergo ” proplonged coasting”…see below?

    4. Were you “triggered” with regular hCG, with Ovidrel (and what dosage of each) OR were you triggered with an agonist (e.g. Lupron).If regular hCG regular was used, the dosage should in my opinion not have been <10,000U. If it was Ovidrel...ideally it should have been 500mcg and in my opinion Lupron trigger is suboptimal.

    The next issue is that of your endometriosis and its relationship to NK cell immunologic implantation dysfunction (see below).

    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
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Induction of Ovulation With Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use
    • 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?
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Why did my IVF Fail
    • 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)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • The Role of Nutritional Supplements in Preparing for IVF
    • Endometriosis and Infertily
    • Treating Ovarian Endometriomas with Sclerotherapy.
    • IVF Egg Donation: A Comprehensive Overview
    • Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site 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.

    Geoff Sher

  • Carrie - March 20, 2016 reply

    Hi Dr. Sher,

    We’ve just had our first try with ivf and it failed. My husband has male factor infertility. My latest test results showed; AMH – 2.13, FSH – 7.6, Estradiol – 50, and last 2 antral follicle counts were 16 and 23. I am 37 and although my gynecologist suggested I am mildy pco (not pcos), our ivf doctor disagrees. All the indicators look good but as the protocol was going along, things seemed to deteriorate. I was on menopur for the first six nights alone and then added in cetrotide over the last 4 nights before triggering with novorel. The cycle started with 16 follicles and resulted in only 8 mature retrieved eggs. All fertilized, but then became poor quality embryos and we ended up with nothing. Our doctor is suggesting we try mini ivf, but my concern is if I have LH sensitivity and the menopur exacerbated the issue, will the mini ivf drugs have a similar impact and fail as well? Is this the right next move? Based on this, could I be LH sensitive? Thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 21, 2016 reply

    I do not believe there is such a thing as “LH-sensitivity”. However, it is necessary to control LH-induced testosterone before and during stimu,ation to atain competent eggs (see below).

    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 (see below) can obviate this effect.

    Severe Ovarian Hyperstimulation Syndrome (OHSS): Women with certain types of absent or dysfunctional ovulation as well as those who have polycystic ovarian syndrome (PCOS) are highly sensitive to gonadotropins and are at risk of developing OHSS. Such women are also more likely than others to produce poor quality eggs/embryos which, they are often led to believe is attributable to an intrinsic egg defect that is characteristic of their PCOS condition. This is not necessarily so. The most likely reason as to why many women with PCOS develop an excessive number of follicles and then go on to produce poor quality eggs/embryos has to do with the fact that, in an attempt to contain reduce the risk of OHSS they are often administered hCG prematurely – prior to the attainment of optimal egg maturation.

    “Prolonged Coasting”: In the early nineties, we introduced “Prolonged Coasting”, a procedure which eliminates the risk of OHSS while allowing the hCG trigger to be deferred for long enough as to allow for optimal follicle/egg maturation to take place. Coasting involves withholding gonadotropin therapy while the administration of GnRH agonist/antagonist is continued. The daily measurement of blood estradiol is continued until the concentration drops below a safe threshold level, at which time HCG is administered (regardless of the number of follicles). When appropriately implemented “coasting” results in the production of good quality eggs/embryos, in circumstances where this might otherwise not have been possible.

    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 promptl

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • 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.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • 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?
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site 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.

    Geoff Sher

    Carrie - March 22, 2016 reply

    Thanks Dr. Sher. How come only estradiol is monitored during a cycle if LH and testosterone can have such a negative effect on the egg’s competency? Is this something that can be monitored during a cycle to ensure the eggs aren’t being compromised by the potentially wrong protocol? Thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 22, 2016 reply

    Serial measurements would not be helpful. The rise is slow and subtle very often.

    Geoff Sher

  • Louise - February 26, 2016 reply

    Dr Sher,
    I have read all of your articles. I am 42 undergoing IVF for secondary infertility ( two living children). I have undergone three cycles in Australia on a GNRH antagonist protocol ( 10 days on BCP, 4 day waiting for menstruation, start FSh on day 1 with orgalutran day 5 onwards, egg retrieval usually day 13). On my first cycle I had 20 eggs collected, 17 mature but only 7 successfully fertilised – I was told the eggs didn’t tolerate ICSI ( I don’t know whether that meant they were over mature, no-one explained it further). Second and third cycles I had 6 fertilised from 11 mature out of 13 collected and then 12 fertilise out of 17 mature from 20 collected I am going day 5 PGD. Out of 3 cycles I had 5 suitable for biopsy – one on day 5 and four day 6 ( hatching blasts). All tested abnormal. I have two frozen blastocysts which were not tested as they were not hatching enough by day 6. I have discounted transferring them. My AMH level is good (20 in Australian measurement), FSh level good for age, I have no health or uterine issues, no PCOS and ovulate with a regular cycle. My first cycle was Gonal f 225 and the next two have been 225 and 300 menopur respectively. I intend to have one last cycle to try and get a comptetent embryo. Would I be better trying Gonal f again rather than menopur? I have not had my testosterone levels tested and don’t know if my lh levels are generally deficient or not. My trigger all cycles has been ovidrel 250. Would a double trigger or changing to Pregnyl be better for me? All cycles I have had the threat of OHSS due to the number of follicles and high estrogen levels.
    I am certainly not a poor responder in numbers but competency is unfortunately my problem. I’d be grateful for any comment you might have.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 26, 2016 reply

    Very respectfully, I personally would use a different approach to stimulation protocol. I do not believe it is ideal to come off a BCP and go directly on tho stimulation (see article below on use of BCP in IVF) as this approach does not allow for optimalt conversion from pre-antral to antral follicles and the latter is necessary for an optimal response to FSH. In my opinion, if a BCP is used to launch a cycle (and I use this approach routinely) it needs to be overlapped with an agonist such as Lupron/Lucrin/Buserelin during the last 3 days of the BCP. A period would ensue and then the agonist would either be withdrawn or replaced by an antagonist (e.g. orgalutron/Cetrotide/Ganirelix) and stimulation with an FSH-recombinant (Gonal-F /Follistim/Puregon)-dominant regime would commence. the trigger would be with 10,000U of hCGu or 500mcg Ovidrel. If there is evidence of ovarian hyperstimulation, “coasting” would be introduced at the appropriate time (see below). I would not use >75U Menopur per day. This I believe would provide the best chance of protecting egg development during stimulation. But even then there can be no assurance that you will produce “competent” eggs because of the age factor.
    I would use Staggered IVF with PGS (with next generation gene sequencing-NGS) and embryo banking of PGS-normal blastocysts.

    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 “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • 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 Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • The Role of Nutritional Supplements in Preparing for IVF
    • IVF Egg Donation: A Comprehensive Overview
    • Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”

    I invite you to call 702-699-7437 or go online on this site 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.

    Geoff Sher

    Louise - February 26, 2016 reply

    Dr Sher,

    Thanks for your comments. Much appreciated.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 26, 2016 reply

    You are most welcome Louise!

    Geoff Sher

  • Angela - January 13, 2016 reply

    Hi Dr Sher, Ive been reading your information with much interest. Im 41 and AMH 1.12 ng/ml (btw the second arrow in the above article needs >15pmol/L). I have had one unsuccessful round of IVF here in Australia. 4 mature eggs (7 collected, all matured but only 4 fertilised). We have added complication of partner having has a Vasectomy 20 years ago (reversal was unsuccessful), and sperm extracted from tubule as epididymis is toughened. Im seeking other opinions. I was on 400 units Gonal F from Day 3 of cycle, started antagonise on Day 7, Luveris added three days day 9, trigger Day 13. I have also been prescribed mho-inositol, melatonin and DHEA (Ive read your concerns about taking DHEA so Im thinking of stopping). Would it serve me to have a consult with your offices for a new protocol? Do you recommend anyone in Australia? Any advice on best stimulation would be greatly appreciated- Ive read about your agonist/antagonist approach starting with BCP and sounds interesting. Thank you.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - January 13, 2016 reply

    Hi Angela,

    Thanks for posting on this site.
    The fact that your husband requites TESA to access his sperm, should not have a negative effect on fertilization.
    With an AMH of 1.2 ng/ml you have moderately severe diminished ovarian reserve (DOR) and I would use a different approach to stimulation. My recommendation would be a modified, robust long pituitary down-regulation protocol coming off a BCP (the agonist/antagonist conversion protocol -A/ACP….see below) with human growth hormone (HGH) supplementation. I would combine this with Embryo Banking and PGS (see below).

    I also would recommend that you discontinue taking DHEA (see below).

    Sorry…I really cannot with confidence offhand recommend anyone for you in Australia.

    Go to the home page of this website and then access my Blog from 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.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Ovarian Stimulation for IVF: Comparing “conventional” use of GnRH antagonists to the Agonist/Antagonist Conversion Protocol (A/ACP)
    • 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.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
    • The Role of Nutritional Supplements in Preparing for IVF
    • Frozen Embryo Transfer (FET): What Does it Involve?
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • PGS-Biopsy for the Assessment of Embryo Numerical Chromosomal integrity (Ploidy): Should it be done on Day 3 or on Day 5-6 post fertilization?
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Launching Ovarian Stimulation with a BCP: How Does it Affect Response?
    • 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?

    I invite you to call 702-699-7437 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.

    Geoff Sher

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