Egg Freezing versus Banking of PGS-Tested Blastocysts, in a Young Woman with prematurely  Diminishing Ovarian Reserve (DOR)?

Questions posed:

Hi Dr Sher, thank you for all that you do in sharing your fertility knowledge. I have learned a lot from your articles and questions/comments. I was also hoping to get your advice: 

I am 32 almost 33 and my fiancé is 27. We just got engaged and are ready to start building our family. I was thinking about freezing my eggs so i have “backup insurance” for myself before trying to conceive naturally. But my initial consultation on day 6 showed: AFC 7, AMH 0.98, FSH 9 MIU/ML. The clinic advised that my numbers were too low for egg freezing and to only freeze/bank my embryos, especially given that we want 3-5 kids.

I have had consultations with 2 local REIs. 

The suggested protocol from REI #1: Estrogen “priming”; Human Growth Hormone (HGH) . Clomid 100 mg, Gonal-F 150 + Menopur 150 + Cetrotide 250mcg, 10,000U hCGu (Pregnyl)”: “trigger”. Protocol from 

The suggested protocol from REI #2: Etrogen priming (no HGH), 300U Gonal-F + 150U Menopur + Dexamethasone + Cetrotide 250mcg,  A “dual trigger” ( Lupron 4mg/hCGu 10000U). One recommended PGS testing and the other did not.1) What protocol would you advise for me?

Thank you!

SPECIFIC RESPONSE!

Indeed, using PGS tested embryos derived from your eggs would be preferable. However, if you have a desire to bank your own eggs for future dispensation, I do not see why this cannot be done, provided that:

1. a) you do not delay unduly, since you need to try to make hay while the sun still shines, 
2. b) you are willing to undergo multiple harvests aimed at banking around 15 mature (MII) eggs and, 
3. c) an individualized protocol is used for ovarian stimulation. I think you need a more “robust protocol of ovarian stimulation with higher dosage of Gonal-F and a lower dosage of Menopur, I am not in favor of the using where clomiphene. I also would launch your stimulation coming off a birth control pill (BCP) without “estrogen priming” and would use an agonist/antagonist conversion protocol and I would “trigger with hCGu (10,000U) and not combined Lupron/hCG) (see below).

You do indeed have early onset of diminished ovarian reserve. However, it is largely age, rather than ovarian reserve that impacts egg quality, provided that an optimal protocol for ovarian stimulation is used given your young age, 2 out of every 3 eggs harvested should still be chromosomally normal….and it is egg , (rather than sperm competency) that is most important. (see below).  Also, It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency”. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy, baby.

COMENTARY:

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 1 out of 2 eggs are chromosomally numerically normal (euploid). The remained have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are competent, and by the mid-forties, less 8 to 9 out of 10 are aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploid and an aneuploid embryo cannot propagate a normal pregnancy

Within hours of the spontaneous pre-ovulatory luteinizing hormone (LH) surge, and also following administration of the human chorionic gonadotropin (hCG) “trigger” shot (given to induce ovulation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining (now redundant) 23are expelled, enveloped by a thin membrane. This small structure comes to lie immediately below the “shell” of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The spermatozoon, in the process of its maturation also undergoes meiosis at which time it too reduces its chromosomes by half. Thus in the process of fertilization the sperm divides into two separate functional gametes, each containing 23 chromosomes such that with subsequent fertilization, the 23 chromosomes in the egg, fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo that has 46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners. 

For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of developing into healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo increases significantly.

While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is rate-limiting factor in human reproduction. It is causal in most cases of “failed implantation” which in turn is responsible for most cases of failed IVF. It causes early miscarriages and is responsible for many chromosomal birth defects such as X-monosomy and Down’s syndrome. . In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain a large amount of cell debris or “fragments” are usually aneuploid and are thus “incompetent”. Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”. At a certain point in the later stage of a woman’s reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 blood follicle stimulating hormone (FSH) level. Such women with diminishing ovarian reserve produce fewer eggs in response to ovarian stimulation. While diminished ovarian reserve is most commonly encountered in women over 40 years of age it can and indeed sometimes does occur in much younger women. A few important (but often overlooked concepts should be considered in this regard: 1. Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo “incompetence” due to aneuploidy 2. DOR: The ovaries and developing eggs of women with diminished ovarian reserve (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced overproduction of male hormones (mainly testosterone). A little testosterone produced by the ovary promotes normal follicle growth and orderly egg development but too much testosterone has the opposite effect. That is why (especially in women with diminished ovarian reserve who often have high LH and increased ovarian testosterone production , the use of ovarian stimulation protocols that fail to down-regulate LH production prior to initiating stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome. Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with diminished ovarian reserve (regardless of their age), unless they receive customized/individualized protocols of ovarian stimulation are less likely to propagate euploid (competent) eggs/embryos.

Selection of the ideal protocol for controlled ovarian stimulation: While NOTHING can be done to lower the incidence of age-related aneuploidy, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocols of ovarian stimulation used.

My Preferred Protocols for Women who have relatively Normal Ovarian Reserve:

1. a) The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (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. Simultaneously, the Lupron dosage is reduced to 5U daily and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is commenced for 2 days. On the 3rd day the gonadotropin dosage is reduced and a small amount of daily menotropin (Menopur 75U daily) is added. Daily ultrasound and blood estradiol measurements are done starting on the 7th or 8th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of 10,000U hCG. And an egg retrieval is scheduled for 36h later.
2. b) The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 125mcg daily until the day of the hCG triggerWhen it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In some cases where the DOR is regarded as severe, I also augment the process with estrogen priming, preferring twice weekly intramuscular administration of estradiol valerate (Delestrogen), starting with the commencement of antagonist injection and continuing for 1 week before commencing gonadotropins and continued until the hCG “trigger. I further recommend that such women be offered access to preimplantation genetic screening (PGS) for4 embryo selection and in some cases, for embryo banking (stockpiling). This is followed in a later hormone replacement cycle with the selective transfer of up to two (2) PGS-normal, euploid blastocysts. In this way we are able to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” , significantly enhancing the opportunity to achieve a viable pregnancy

The following Ovarian Stimulation Protocols which in my Opinion best Avoided:

1. a) Microdose agonist (e.g. Lupron) “flare” protocolsb) High doses of LH/hCG-containing fertility drugs (E.G. Menopur).
   c) Protocols that incorporate supplementation with male hormones (e.g. testosterone)
   d) Supplementation with DHEA
   e) Clomiphene citrate or Letrozole which cause an elevation in LH and thus increase ovarian male hormone (testosterone and androstenedione output.
   f) “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel e.g. 250mcg of Ovidrel rather than 500mcg)
   g) “Triggering” women who have large numbers of follicles using an agonist such as Lupron, Superfact or Buserelin.

Preimplantation Genetic Screening (PGS):
The introduction of preimplantation genetic screening (PGS) for the first time permits identification of all the chromosomes in the egg and embryo such that we can now far better identify “competent” (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process. This additional tool has better equipped us to manage cases with DOR. In my opinion, next generation gene sequencing (NGS), currently represents the most reliable method for performing PGS

Please visit my 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. Here are a few of the articles that you might wish to access 

• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS) Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol 
• Egg Banking
• 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)
• 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): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
•  Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
• Preimplantation Genetic Screening (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.
• Embryo Mosaicism”: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• How Many Embryos should be transferred: A Critical Decision in IVF.
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.