Dr. Sher Blog

Official blog of Dr. Geoffrey Sher

How Old is Too Old to Do IVF Using Your Own Eggs?

by Dr. Geoffrey Sher on March 25, 2018

There is little doubt that age is a very important determinant of IVF outcome.  This is mainly because a woman’s eggs undergo deterioration in quality as her age advances to and beyond her mid 30’s.  Remember, eggs have been in the woman’s ovaries ever since she was incubating in her mother’s uterus.  Thus, after a certain period of time….when she reaches her mid 30’s, a wear and tear effect increases the likelihood of chromosomal abnormalities that become unmasked with the maturation process.  The latter occurs with the LH surge that precedes normal ovulation and the administration of hCG to induce ovulation.  In this regard, it is important to recognize that it is predominantly the egg (and not the sperm) that determines the chromosomal integrity (karyotype) of the embryo and an embryo with an irregular number of chromosomes (aneuploid) is incapable of propagating a normal baby.  In fact, aneuploid eggs often fail to fertilize, and those that do, either fail to divide normally or will implant defectively, resulting in an early pregnancy loss.  Alas, in some cases the embryo might well attach and develop into a baby with a severe chromosomal abnormality that is often incompatible with survival but in some cases (such as with Down syndrome) might well survive through birth.

 

Here are a few general statistics that should help you understand the impact of age on embryo “competence” (ability to propagate a healthy pregnancy).  Up until the early 30’s about 1:2 eggs and embryos are aneuploid.  At 35-39 about 3 in 4 or 4 in 5 are aneuploid and by age 40, about  5 out of 6 eggs are chromosomally abnormal.  By the mid 40’s about 9 out of 10 eggs/embryos are aneuploid.  To make matters worse as the woman ages beyond 35 she gets ever closer to the menopause and the number of eggs that become available for harvesting in IVF declines progressively.  Thus, with a greater percentage of embryos being aneuploid (“incompetent”) and fewer embryos available, it should come as no surprise that IVF success rates decline progressively with advancing age beyond the mid 30’s and then quite precipitously in the mid 40’s.

 

There is another point worth emphasizing and that is that an embryo that is numerically, chromosomally normal (euploid) has an excellent chance of propagating a viable pregnancy regardless of the age of the woman from whose ovary it was harvested.  This means that the mechanism whereby advancing age progressively reduces the likelihood of a successful IVF pregnancy is the result of the declining potential in older woman to propagate euploid eggs rather than through progressive diminution in the overall quality of all her eggs.

 

Aside from the inevitable age-related decline in egg/embryo competency, there is also the fact that as women get older the amount of available eggs in their ovaries also diminishes. This diminution in ovarian reserve (DOR) is also associated with increased biological activity of pituitary LH which increased ovarian testosterone production to the point where it compromises egg development, further increasing the propensity for egg-embryo aneuploidy. Women who have DOR are also far more vulnerable to any ovarian stimulation protocol that fails to regulate LH-induced testosterone production.

So, what can be done to offset some of the above inevitabilities?

First:  It is important to counsel older patients on the inevitable consequences of deliberately delaying treatment of infertility.  I always counsel my older patients that the biological clock cannot be reset and that they should be both decisive and proactive when it comes to commencing IVF treatment.

Second: Since there is nothing anyone can do to reverse the effect of advancing age on egg/embryo aneuploidy, the only way we as physicians can attempt to influence the process is by trying to limit exposure to excess ovarian testosterone.  In that my opinion this requires:

  1. Avoidance of ovarian stimulation protocols that increase pituitary LH release, e.g. short agonist “flare “protocols; administering drugs that promote additional LH release (clomiphene/Letrozole)
  2. Avoiding exogenous male hormone administration during ovarian stimulation (testosterone or DHEA)
  3. Avoiding exposure to additional exogenous LH or hCG (which acts like LH to cause increased ovarian testosterone production

 

Third: Seriously considering the option of “embryo banking”.  Here we attempt to arrest the biological clock by banking the older woman’s embryos over a number of consecutive cycles in order to increase the number of available embryos for transfer.  Such embryo banking can be further embellished by testing each embryo for its chromosomal integrity using Preimplantation Genetic Sampling (PGS) and then stockpiling the normal embryos for subsequent dispensation to the woman’s uterus.  With this in mind, older women, as well as those who regardless of age have diminishing ovarian reserve, are in ever increasing numbers seeking access to embryo banking in the hope of so extending their reproductive potential.

 

Fourth: Finally, for those women for whom the biological clock has run out, there is always the option of egg donation.  In my experience, this is an optimal option through which couples can still enjoy all the joy and happiness associated with family.

Share this post:

Related Posts

Take a also a look at these posts

18 comments

Leave A Reply
  • tora - August 14, 2018 reply

    Dear Dr Sher,
    I am 41 years old and have over the last 6 months done 3 ivf cycles where we banked all the embryos to do PGS testing. We had 7 embryos to test and I got the results yesterday – all had chromosomal abnormalities. I’m devastated as I had really expected to have at least 1 normal to transfer, as had my doctor. I had a termination beginning of the year (after having conceiving naturally) after finding out that the baby i was carrying had Down’s syndrome. I have a healthy daughter who was born when I was 39. She was conceived naturally.
    I am now completely at loss at what to do. Is it worth examining the embryos we have to see if any of them can self-correct? Our clinic doesn’t do this so I would need to go elsewhere… Or do we do m0re rounds of IVF with my own eggs and hope we get lucky or is it doomed and do we need to accept it won’t happen? I’m open to egg donation- would that be the best route for us?
    Many thanks for your time.
    Kind regards
    Tora

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 14, 2018 reply

    Hi Tora,

    At 421y the risk of aneuploidy of embryos is high…perhaps only about 1:10 would be normal anyway. However, aside from age, the protocol used for ovarian stimulation can in my opinion, also affect the likelihood of meiotic aneuploidy. Thus ,since you are likely running out of time on the “biological clock”, I would suggest trying again, sooner rather than later but using only after reviewing/revising the protocol used for ovarian stimulation.

    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). 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
    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
    • Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
    • IVF Egg Donation: A Comprehensive Overview

    If you are interested in 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 - August 8, 2018 reply

    Dear Dr. Sher,

    Is 42 too old for IVF? I had my first missed miscarriage at 39 and my second at 40. I have been told by my doctor that there is now no chance of conceiving naturally and that my only possible hope is IVF, but my partner does not think we should do it as he doesn’t think it will work. Should I close the door on having my own baby?

    Many thanks for your time.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 8, 2018 reply

    Younger is preferable, but depending on other factors, 42y is not too old!

    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). 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
    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
    • Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
    • IVF Egg Donation: A Comprehensive Overview

    If you are interested in 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

  • Ana - August 7, 2018 reply

    Hi Doctor:
    We just had our 4th IVF, first two cancelled due to premature ovulation, 3rd one follicle with no egg in Egg retrieval and 4th 4 eggs, 3 mature, non fertilised with PICSI. I have extremely low AMH (1,64pmol) and my husband 37% DNA fragmentation. On first and third cycle we got 1 follicle, second cycle 2 follicles, 4th cycle 5 follicles on long protocol, 600 gonal F and buserelin, following your suggestion I took 500mcg ovidrel. We triggered after 16 days of injections. Why they didn’t fertilise? is it due to egg quality, sperm quality? what can we do different next time? Thanks

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 7, 2018 reply

    Hi Ana,

    In my opinion, this is likely due to a combination of your diminished ovarian reserve (DOR) and the protocol used for ovarian stimulation.

    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). 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
    Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
    • Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
    • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
    • IVF Egg Donation: A Comprehensive Overview

    If you are interested in 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

    Ana - August 8, 2018 reply

    Hi Doctor:
    On our 4th IVF we followed your guidelines and it really improved a lot. We got 5 follicles and 3 mature, I didn’t have any LH surge and down -regulation really worked even though the lining was really thin. But my question was why do you think none of the eggs fertilise with ICSI? what would you do different?
    Thanks

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 8, 2018 reply

    I would need to know much more about your case to comment authoritatively.

    Geoff Sher

    Ana - August 9, 2018 reply

    Thanks

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 9, 2018 reply

    You are welcome Ana!

    Geoff Sher

  • JP - July 29, 2018 reply

    Hi Dr Sher

    Thank you for your informative website & all the information on offer.

    I am now 43 years old & my wife has turned 40 in January of this year. We live in South Africa and have a healthy son of almost 9 years old. We have been trying actively to conceive for the past 3 years. We have been attending fertility clinics for the past 2 years and we are struggling with diminished ovarian reserve. We are aware of the issue that age plays in infertility. My wife is also hypothyroid and has been on treatment (Eltroxin) for the past 5 years. The TSH levels have been stable at between 1.5 & 2.5 over the years.

    After a few ovarian stimulation cycles with clomiphene and later Menopur with no success, we were advised to strongly consider donor eggs. We embarked on the donor egg cycle about 9 months ago but we were also not successful. Embryos were frozen for possible later use.

    On various different occasions during ultrasound examination, the comment was made by different doctors that the endometrial lining was a bit thicker than expected but no specific concerns were raised at any time. Even during the donor IVF process the endometrial thickness was evaluated and deemed favorable for embryo transfer into the uterus. As mentioned, this donor IVF attempt failed.

    We have now embarked on “egg banking”. Endometrial thickness was measured at between 6 & 8mm on day 2/3 after the first day of menstruation. Two hysteroscopies were performed in the past with no abnormalities found and biopsy showed no malignant or abnormal material. One egg was retrieved in the first cycle and thereafter a 30mm ovarian cyst was diagnosed with elevated estradiol levels.

    We have opted for conservative treatment of the ovarian cyst and we are now awaiting my spouse’s next menstrual cycle to start. We remain positive for a positive outcome.

    My first question is regarding the thickened endometrial lining during early follicular phase and its possible negative impact on embryo implantation, whether natural, IVF or donor IVF. My second question is regarding hypothyroidism & fertility: what are the ideal therapeutic TSH levels to maximize our chances to conceive and should we be monitoring T3 & T4 levels very closely also?

    If possible, can you share your thoughts with us regarding the above mentioned facts & questions.

    Warmest regards.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - July 29, 2018 reply

    As long as there is no endometrial pathology…a thicker than normal endometrium is in my opinion inconsequential!

    Unless the elevated TSH is accompanied by abnormal T3/T4 , it will in my opinion, NOT adversely affect IVF outcome. However,Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies.
    The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.
    It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.
    Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

    Geoff Sher
    PH: 800-780-7437 for a Skype consultation
    The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment.

  • Mrs. SFBJ - April 11, 2018 reply

    We am considering recurrent miscarriage investigations (in UK), and possibly a donor egg cycle. We had eleven natural conceptions 1998-2010, one live child, a son in 2000
    (I was age 34 at conception), now he is age eighteen and we suffered ten miscarriages, two early ones, then our son, and eight further miscarriages (two of those early both with some prevention treatment). No diagnosis from Aberdeen or London (Dr L Regan) other than one miscarriage was a trisomy. We plan to do the comprehensive implantation package of investigations at Reproductive Health Group private clinic near Liverpool. We have never done a hysteroscopy exam and this is included in the investigations with NK biopsy and are a bit concerned that scaring or growths may be present (three of the seven medically induced procedures resulted in three D&C for excessive bleeding. My sister, suspects I may have factor 13 deficiency clotting disorder, so we will get that checked as well.

    My question is whether there would be any hope for us, do you think, of using a donor egg….and our now adult son as our sperm donor, as we wish to avoid our own gametes. I am now 53, have BMI of 22, and cycle every 29 days, and still seem to ovulate on full moons but may still have peri menopause FSH and AMH maybe.

    The other question is why I can I find no clinic or researcher even remotely interested in our case for research to prevent others suffering so much, (gene testing).

    Obviously, we are hoping our son may have our only good gene combination and a young egg may overcome secondary infertility to produce a genetic grandchild to raise.

    Age 53 is likely the last year to find a clinic willing to do a donor egg cycle, and these clinics are hard to find, especially with our miscarriage history and wish to use our sons donor sperm, though I may have found two clinics.

    The obvious answer would be to wait for our son to marry and have grandchildren, but six of our later losses were 9-15 weeks in measurement, four of those 13-15 weeks measurement, and the wait maybe another ten years or more….after seventeen years since his birth of trying.

    What are your thoughts?

    PS several pregnancies aspirin was tried, and in 2007 blood thinning injections (Dr L. Regan….though clotting issue not detected by her investigations), and 2010 progesterone pessaries and steroid pills ( I begged for these as
    I read Dr Quenby got some results trying these…prednisalone 20 mg) but these were the two under seven week losses after our son.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 11, 2018 reply

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

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

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

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

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

    I strongly recommend that you visit 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
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF

    If you are interested in 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

  • Audrey - April 10, 2018 reply

    Dear Dr. Sher – thank you for your excellent and honest guidance into fertility treatments. I am 39Y, have never been pregnant and had 4 failed IVF treatments over 10 months in 2017. My most recent ovarian reserve results (Mar-2018) were AMH 2.44/FSH 9.3/Estrogen 60 and I am considering another IVF attempt. Note these levels are bouncing around – i.e. in Feb-2017 the levels were: AMH 2.1/FSH 14/Estrogen 71; in Sept-2017, the levels were AMH 1.9/FSH 18.2/Estrogen 53.

    My husband’s sperm tests prior to starting IVF were normal. Hysteroscopy exam prior to IVF revealed no major issues. In each IVF treatment, we had low fertilization rates and our embryos consistently failed to make it to a ‘healthy’ Day-5 blastocyst stage. The first 3 cycles were with an antagonist protocol + HCG trigger; the 4th cycle was a with a down-regulation protocol.
    #1 Mar-2017: 13 eggs retrieved, 11 mature, 6 fertilized, 2 transferred on Day-3
    #2 May-2017: 11 eggs retrieved, 9 mature, 4 fertilized, no embryos made it to transfer
    #3 Aug-2017, following a 30-day testosterone protocol: 15 eggs retrieved, 11 mature, 5 fertilized, 1 remaining embryo in “early-blast” stage transferred on Day-5
    #4 Nov-2017: 6 eggs retrieved, 2 mature, 1 fertilized and transferred on Day-3.

    My RE concluded that I have a significant egg quality issue given the persistent outcome of low fertilization rates, and repeated failure of the embryos to progress to a ‘normal’ Day-5 blastocyst stage. He has recommended that we move to egg donation.

    Would you concur with my RE’s conclusion Dr. Sher?
    Also, if we do proceed for another attempt, not all other RE’s in my area offer PGS – we did not use PGS in any previous attempt since we never had enough embroys to warrant it, but given my history of poor quality embryos, should we consider PGS as a necessary tool in the IVF. process for us?

    Finally, prior to each IVF round, I was on a daily regime of 2 x 100 CoQ10, and 3 x 25g DHEA. I am currently on a regime of 2 x 200 CoQ10 and 2 x 25g DHEA. I note in your blog above that you advise against using DHEA during ovarian stimulation – does that advice hold prior to stimulation also?

    Many thanks for your insights.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 10, 2018 reply

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

    • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
    • The Fundamental Requirements for Achieving Optimal IVF Success
    • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers should be the Standard of Care in IVF
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF?
    • The Role of Nutritional Supplements in Preparing for IVF
    If you are interested in 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 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

  • Nur - April 1, 2018 reply

    Hello Dr. Sher

    I am 41 years old, with what it seems good ovarian reserve (at CD 3 AMH:3.1, FSH: 5.5, LH: 4, Estradiol:36). A year an a half ago we had a natural pregnancy that ended up in miscarriage at 6 weeks. Three months ago we went through IVF with an antagonistic cycle and Grnh-a trigger (the dr thought I was responding “too well” to the medications and we should not risk OHSS) and we got 10 eggs retrieved, 9 MII, 8 fertilized, 8 got to blastocyst. After PGS all of the embryos came out aneuploid.

    We just finished another antagonistic cycle with same trigger and got 13 eggs retrieved all at MII stage, 11 fertilized and 8 made it to blastocyst. This time, the doctors also observed that the 2cm bloody cyst I had in one ovary for some months it was looking now more like an endometrioma. I would not be surprised of having some endometriosis as my periods for the last 6 years have been quite painful. We don’t know yet the result of the PGS for the last batch of embryos because we are doing egg banking for another cycle before analyzing them.

    My question to you Dr. Sher is if you recommend doing another antagonistic cycle with GrnH-a trigger for this third cycle as our doctor suggests (based on our good blastocyst rates). Given my age and my previous responses it would seem that our problem is the aneuploidy rate in the embryos. Is there any ovarian stimulation protocol that would increase the quality of the eggs more than other, especially under the suspicion of endometriosis? Is there any benefit on using a HCG trigger instead of Grnh-a trigger to increase egg quality (we are planning on FET anyway to avoid OHSS)? Or any other thing aside of protocol that one can do to increase the quality of the eggs like exercise and supplements? Finally, are there any tests that you would recommend to confirm or discard the endometriosis condition and prepare for eventual problems with implantation (eg. NKa cells)?

    I am asking all of this because our doctor thinks that at this point is a game of numbers and the stimulation protocol will not change things. I would love to hear your opinion on the matter. If we can learn from the failures and design a smart approach to eventually get successful we would love to do so. If the only think that we can do is try again, it would also be good to know. As it would be good to know what is the aggregated number of cycles that a 41 year old needs in average to be successful with her own eggs.

    Thank you very much for your extremely insightful blog. It has helped us immensely to understand many of the concepts of this journey.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 1, 2018 reply

    Very respectfully Nur,

    I wish to point out that at 41y, because of the effect of age, most eggs/embryos will be aneuploid and there is nothing that can be done to change that reality. This having been said to have had 16 blastocysts with NONE being euploid, is not right. In my opinion, 2 things contributed to this unusual result. The first is the protocol used for ovarian stimulation and the second is (in my opinion), the use of an agonist “trigger” (see below). Also, I strongly urge that the endometrioma be eliminated (surgically or by sclerotherapy). Another issue is to recognize that 1/3 of women who have endometriosis also have an immunologic implantation dysfunction linked to “activated” uterine natural killer cells (NKa) which needs to be identified, quantified and addressed prior to ANY ET…in my opinion.

    So what is needed is a) addressing the endometrioma and looking for an IID. b) This should in my opinion be combined with careful review and revision of the protocol used to stimulate your ovaries followed by a 10,000U hCG “trigger” (or Ovidrel 500mcg). Thereupon all day 5-6 blastocysts should be biopsied and PGS-normal blastocysts should be vitribanked for future FET to a uterus. If an IID is detected, then targeted immunotherapy with Intralipid/steroids/heparinoid (Lovenox) should be used in advance of, and following FET.

    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). 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

    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
    Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
    • Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
    • Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
    • Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
    • Treating Ovarian Endometriomas with Sclerotherapy.
    • Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.

    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

Ask a question or post a comment