IVF: Immature and Post-mature Eggs: What does this mean and how can it be prevented?

One commonly hears patients undergoing IVF report that they had too many “immature eggs”, and inferring that had more time been allotted to ovarian stimulation and the administration of the “trigger shot been delayed by a day or more, this might not have happened. Nothing could be farther from the truth. In fact, the duration of ovarian stimulation is rarely the cause of egg “immaturity”. More often than not can be attributable to the use of a sub-optimal protocol for ovarian stimulation especially in cases of advanced maternal age, diminished ovarian reserve and in cases of polycystic ovarian syndrome (PCOS). In this presentation, I will discuss the implications of “Egg Maturation“, its role in IVF outcome and how to optimize the yield of mature eggs.

Within 38-42 hours of the onset of the spontaneous LH surge in normally ovulating women as well as after the administration of human chorionic gonadotropin (hCG) to women undergoing ovarian stimulation with fertility drugs, the total number of egg chromosomes in the egg nucleus is reduced through a process known as meiosis or “maturational division”. The purpose of meiosis is to halve the total number of chromosomes from 46 (the normal human genomic number) to 23 by expelling them in a membranous envelopment known as the 1st polar body (PB-1). The PBI comes to lie in a narrow space (the viteline space) which is located between the egg’s outer shell (zona pellucida) and the membrane that surrounds the inner egg substance (the oolema) where it can often be identified microscopically. The PB-1 soon undergoes degeneration and within a few days of meiosis having been completed, disintegrates and absorbs completely. An egg with a microscopically detected PB-1, is referred to as being “mature” (M-II). An “immature” egg (M-1) is one that has fails to undergo maturational division (meiosis) and thus has all 46 chromosomes intact. In this form, the immature egg is incapable of propagating a healthy embryo (see below).

In order to be capable of fertilizing an egg, the sperm must likewise undergo meiosis, the purpose of which is to reduce its chromosome number from 46 to 23. Upon fertilization of the M-11 egg with a mature spermatozoon, the resulting embryo will have a chromosome number equal to the combined contribution by both egg and sperm. The objective is for fertilization to involve an egg and )spermatozoon that each have precisely 23 chromosomes, such that the resulting embryo will contain precisely 46 chromosomes (euploid) and thus be “competent” to propagate a normal baby. Embryos with less or more than 46 chromosomes (aneuploid) are “incompetent” and arrest during development, fail to implant normally, be lost in early miscarriage or will result in a chromosomal developmental defect such as Down syndrome. More than 70% of cases, embryo aneuploidy (“incompetence” is the direct result of the egg (rather than the sperm) undergoing abnormal maturation that results in there being more than or less than 23 chromosomes, prior to fertilization.

The confirmation microscopically that an egg is “mature”, in no way ensures that it has precisely 23 chromosomes. In fact, in humans, more often than not, most M-II eggs will indeed have more than or less than 23 chromosomes (aneuploid eggs) and accordingly be incapable of propagating euploid embryos following fertilization. This propensity increases with advancing age and in certain conditions such as polycystic ovarian syndrome (PCOS”) but can also be aggravated by the use of “suboptimal protocols” for ovarian stimulation (especially when it comes to women who have diminished ovarian reserve). This is why it is so important to be highly individualized in selecting the protocol used for ovarian stimulation in such cases. Aneuploid eggs are incapable of propagating “competent”, euploid embryos.

To recap….the detection by microscopy, of a PB-1 situated immediately under the egg’s zona pellucida, indicates that maturational division (meiosis) has been completed. BUT it does NOT provide assurance that chromosome segregation has been orderly (i.e. that precisely 23 chromosomes remain in the egg nucleus) and that the egg is “euploid”. The presence of even one more or one less than 23 chromosomes is referred to as egg “aneuploidy”… a condition that almost always results in failed embryo development failed implantation, miscarriage or chromosomal birth defects such as Down’s syndrome. As it turns out, even in younger women a half to one two thirds of MII eggs are aneuploid and this incidence increases rapidly with advancement in age beyond 35 years.

It is by and large the chromosomal integrity of the egg, rather than the sperm that determines embryo “competency”. Thus egg “competency” is an essential prerequisite for the propagation of a viable embryo and a healthy baby.

Another interesting fact is that an embryo that fails to reach the blastocyst stage is almost invariably aneuploid, “incompetent” and is thus are doomed from the get-go. On the other hand, embryos that do make it to the blastocyst stage, while being much more likely to be euploid are often aneuploid and “incompetent”.  Even in young women with normal ovarian reserve, less than 50% of blastocysts will be aneuploid and percentage increases progressively with advancing age. And this incidence can be further influenced by the protocol used for ovarian stimulation as well as the timing and dosage of the hCG used to “trigger” egg meiosis, at the end of the stimulation process. When the hCG trigger is administered too early or too late or too low a dosage of hCG is administered (5,000U rather than 10,000U of hCGu or 250mcg rather than500mcg of hCG-Ovidrel) , the egg might not be developmentally positioned to undergo orderly meiosis. The result could be an increase in the percentage of immature (M-1) or mature M-2 (but aneuploid), eggs.

The terms “immature” and “post-mature” as applied to eggs , is thus often erroneously interpreted as meaning that the eggs were either harvested too  early , and that performing the egg retrieval a day a day or two earlier would have prevented this from happening. This suggestion infers that MI eggs result from their being harvested before they were developmentally ready to enter meiosis. This inference is completely erroneous. In fact, as previously stated, an M1 egg could just as easily have resulted from delaying the hCG trigger too long or from using the wrong timing or dosage of. Likewise a “post-mature” egg can result just as readily from administering hCG too early as too late. For these reasons, the terms “immature” and “post-mature,” as applied to eggs, should be supplanted by the term “dysmature” which simply implies that the M-1 or M-2 egg in question is maldeveloped, aneuploid and “incompetent”.

Finally, it is important to bear in mind that severely aneuploid eggs often remain densely attached to the inner wall of the follicle and fail to loosen sufficiently from surrounding cells during follicle aspiration. When this affects most or all available follicles, this condition is often referred to as “Empty Follicle Syndrome (EFS)“. It is an erroneous diagnosis because a follicle requires an egg to grow. The more likely explanation is severe egg “dysmaturity”.

12 Comments

Charlene Zarb

I have just had to abandon my first ivf cycle after egg retrieval. My last scan before triggering showed I had less follicles than expected (at 13 day of stimms) with 3 follicles a bit larger than 17mm, other 3 of around 16mm and a few smaller ones. They only managed to get four eggs at retrieval, all of them abnormal and hopeless. My AMH levels are pretty average for my age, 1.9 at 33 years so it was a real shock. I’m still waiting for my follow-up consultation. What could have happened? Does this mean that my egg quality is very poor and will never improve? I remember being told at my base scan that I was a bit suppressed. I had been on bcp for almost three months prior to my cycle. Could this have been a reason for the quality of my eggs? What should I do next? Thank you

reply
Dr. Geoffrey Sher

It could be related to the protocol used for ovarian stimul;ation.

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

reply
Evelyn

Hi Dr. Sher,
I am hoping you maybe able to provide some insight. I am now 39 years old, healthy and active. I do have diminished ovarian reserve based on blood values obtained when I was 37. I have been trying to conceive for three years with donor sperm (well tested). I had 7 failed IUI’s before turning to IVF. I have been through 5 cycles of IVF and have come up with 2 PGS normal embryos only. I generally have 5-7 follicles per cycle. With each cycle though, my total follicle count has been decreasing despite increasing dosing of Gonal F. I have been on a mini-stim protocol of Gonal F (initially 150IU and worked up to 300 IU), Menopur 150, and provera and later in the cycle adding in cetrotide. The final cycle we also tried growth hormone and that was the worse cycle of them all as I had 5 follicles and my doctor was only able to retrieve one egg. The first PGS normal embryo resulted in a miscarriage at 8 weeks after seeing a normal heartbeat. The second PGS normal embryo resulted in a chemical pregnancy. I have taken plenty of supplements including DHEA, CoQ10, and vitamin E during my cycles. I took a prenatal all throughout. The second pregnancy I also took 81mg aspirin daily. I’m out of PGS normal embryos now. I have one untested embryo left. I don’t know if I should keep going through IVF cycles even though I may only get one to three follicles) or if I should give up at this point. We have not investigated immune issues with implantation but I’m unsure the frequency with which that is diagnosed and if it is worth going through another three IVF cycles to potentially, maybe get 1 more PGS embryo. Thank you for time.

reply
Dr. Geoffrey Sher

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

reply
Tunde

Hi Dr Sher,
I am a very grateful avid reader of your blog and observed that you recently addressed the impact of ovarian cysts on ivf cycles. I am hoping you are able to offer some advice on whether the presence of one cyst in each ovary measuring about 1.2cm can pose problems starting on controlled ovarian stimulation after a cycle starting with birth control pills and overlapping lupron before a switch to an antagonist as in your A/ACP protocol. I am earnestly looking forward to your response.

reply
Dr. Geoffrey Sher

It depends whether these are functional cysts or not. Ordinarily,a small cyst like that, if functional and detected at the start of the period should not pose a problem, provided the basal blood estrogen (E2) is <70pg/ml.

Geoff Sher

reply
Aur

Hi Dr Sher
I have been reading your blog and listening to some of your Youtube video with great interest.
I am 40 and live in London UK- I had a first IVF cycle in Oct 2017 which resulted in missed Miscarriage at 12 weeks in January, baby stopped growing at 9 weeks, this was due to Trisomy 22 (we did some tissue analysis)
The short protocol followed was 225 UI Bemfola (FSH/Gonal equivalent I think) starting day 2 of the cycle and then Cetrotide starting day 6, then trigger of Ovitrell 500.
We got 3 mature eggs, 3 fertilised, 1 “perfect” grade embryo that was transferred on day 3 and 2 other embryos of lesser grade that did not make it to day 5.
I am now thinking of doing 3 cycles back to back to increase chances and accelerate things due to my age , I have low ovarian reserve. I am on CoQ 10, conception supplements and Vitamin E &D
The clinic I went to is specialised in Mild IVF / Mild stimulation and say they prefer quality over quantity of eggs retrieved and are considering similar protocol for next IVF (mild FSH + Cetrotide at 6 days…)
What protocol and doses would you recommend for 40YO with low ovarian reserve, also are there any clinic you would recommend in London UK or with whom you have worked directly?

reply
Dr. Geoffrey Sher

Thank you!

I cannot lay out the protocol in detail here. That would not be appropriate but here are a few guide lines!

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

reply
Holly

I just completed my first IVF cycle and took HGC trigger at exactly the right time down to the minute. When they went in for my retrieval I had four follicles alll above 15mm. they said they could see I was literally ovulating in the moment and this could not get any eggs except for one that was immature. What happened? The clinic is brushing it off as normal but we are devestated as we basically lost this cycle

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Dr. Geoffrey Sher

It sound to me like possible “premature luteinization”.

Premature luteinization (“premature LH surge”) occurs when prior to the planned initiation of the hCG trigger, a progressive rise in LH, irreversibly compromises follicle and egg development and maturation. It is not a sporadic isolated event. It comes as a culmination of a series ovarian events, occurring mostly in susceptible women (i.e. usually older women and those with diminished ovarian reserve. It is more likely to occur when the protocol used for ovarian stimulation has failed to maintain LH activity at a low level prior to and throughout the ovarian stimulation process. Once it occurs in any given stimulation cycle it cannot be switched off by changing the stimulation in progress or by administering GnRH antagonists (e.g. Ganirelix/Cetrotide/Orgalutron) midway in the cycle in the hope that this could rescue the eggs under development. It is my opinion, once premature luteinization commences, the cycle is doomed and outcome is doomed to fail. The condition increases the likelihood of premature ovulation, failed release of eggs during needle-guided egg retrieval (so called “empty follicle syndrome” and the incidence of egg/embryo “incompetence” (chromosomal aneuploidy).
This situation is most commonly seen in older women and in women who have severely diminished ovarian reserve. In many cases its effect can be prevented through implementation of strategic and individualized protocols for controlled ovarian stimulation (COS) coupled with optimizing the type, timing and dosage of the “hCG trigger shot.”
Normally, following optimal ovarian stimulation, the “trigger shot” is given for the purpose of it initiating meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).
Older women, and women with diminished ovarian reserve, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.
Women with the above mentioned conditions often have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”
The developing eggs of women who have increased LH activity (older women, and women with diminished ovarian reserve) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrozole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.
The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG or Ovidrel can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

Geoff Sher

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Naz

Hello Dr. Sher,
Thank you for making this forum available for your valuable advice. I am 35 years old with FSH 10.6, Estradiol 61.9, AMH 1.9 (Vit D was ~ 11, now at 40 after high dose treatment).
I am preparing for my second COS in 2-cycle embryo banking. My protocol was
BCP for 2 weeks, 5 days after last BC start 300 IU Gonal F, 150 IU Menopur, Clomid 100mg. On 6th day increased Menopur and started Cetrotide. Total 9 days of stim. Trigger HCG Leuprolide 1000iu/4mg.
At retrieval I had 16 follicles > 14mm, 11 eggs, 9 mature, 8 fertilized, 5 blasts, 2 PGS normal, 2 PGS abnormal, 1 PGS indeterminate.
For my second COS my Doctor wants to make the following modifications: Luteal estrace cycle day 20, add HGH COS day 7, add FSH with trigger, keep the rest the same as the last protocol.
I am disappointed that she was unable to retrieve eggs from 5 of the >14mm follicles, and I’m aware that there is no such thing as an empty follicle. What modifications would you recommend to my protocol to yield a greater number of mature eggs?
Thank You – Naz

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Dr. Geoffrey Sher

Here is the protocol I advise for women, <40Y who have adequate ovarian reserve.
My advice is to use a long pituitary down regulation protocol starting on a BCP, and overlapping it with Lupron 10U daily for three (3) days and then stopping the BCP but continuing on Lupron 10u daily (in my opinion 20U daily is too much) and await a period (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst and simultaneously, the Lupron dosage is reduced to 5U daily to be continued until the hCG (10,000u) trigger. An FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is started with the period for 2 days and then the gonadotropin dosage is reduced and a small amount of menotropin (Menopur---no more than 75U daily) is added. This is continued until US and blood estradiol levels indicate that the hCG trigger be given, whereupon an ER is done 36h later. I personally would advise against using Lupron in “flare protocol” arrangement (where the Lupron commences with the onset of gonadotropin administration.
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF
• “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .

*FYI
The 4th edition of my newest book ,”In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoffrey Sher MD

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