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Egg Maturation in IVF: How Egg “Immaturity,” “Post-maturity,” and “Dysmaturity” Influence IVF Outcome.

by Dr. Geoffrey Sher on April 10, 2017

There is a great deal of confusion when it comes to defining egg “quality.” Most people interpret terms such as “mature/immature/post-mature” eggs as implying that the timing of egg retrieval was off. This is, at best, a gross over-simplification and at worst, dangerously misleading.

Egg Maturation involves reduction of the number of chromosomes from 46 (the diploid number) to 23 (haploid) through reproductive division (meiosis) that begins 36-42 hours prior to ovulation or egg extraction. The fact that meiosis has occurred can be confirmed through the detection of a small membranous body under the outer envelopment (zona pellucida) of the egg, known as the 1st polar body (PB-1) which contains chromosomes that are discarded with meiosis.

In the natural ovulation cycle meiosis is triggered by a spontaneous LH surge (measurable by home ovulation testing) which precedes ovulation by 38-42 hours, or so. In ART cycles, meiosis can be triggered through inducing the same LH surge by way of administering a GnRH agonist (GnRHa) such as Lupron or Buserelin or through the administration of hCG (e.g. Pregnyl/ Profasi/ Novarel/ Ovidrel) that acts similar to LH.

Clearly, in order for an egg to fertilize, it must first mature (M2). Ordinarily, an M1 egg cannot fertilize normally. However in some cases, extended culture for several hours prior to fertilization will allow M1 eggs to undergo meiosis in the petri dish and become M2s.

So, a mature egg (M2) is one that has gone through meiosis while an “immature” egg (M1), has not. However, the fact that all M2 eggs have indeed undergone meiosis, does not imply that the meiotic process was orderly. In fact, the vast majority of M2 eggs are aneuploid (i.e. they do not have the exact required haploid number of 23 chromosomes.) Upon fertilization, such aneuploid embryos that have more or less than 46 chromosomes will be “incompetent” and unable to propagate a healthy pregnancy. They will either arrest during development, fail to attach to the uterine lining, be lost as early miscarriages or develop into chromosomally compromised babies (e.g. Down syndrome). One of the largest “misconceptions” is that all M2 (mature) eggs are equally competent to fertilize and propagate viable embryos. Nothing could be further from the truth.

Since all M1, and most M2 eggs are aneuploid and “incompetent”, use of the term “immature” to differentiate between “competent” and “incompetent” eggs can be highly misleading. In addition, some M2 eggs are incompetent because they are “post-mature” Thus the term “dysmature” would better characterizes the status of such eggs.

While advanced maternal age is by far the commonest cause of egg dysmaturity, implementation of suboptimal protocols for ovarian stimulation can have the same effect. And here, independent of age, women who have diminished ovarian reserve (DOR) are the most vulnerable and here, the combination of advanced age + DOR is the most lethal combination of all.

I have in the past repeatedly pointed out that in my opinion, over-exposure of developing eggs/follicles to excess LH-induced testosterone can and often does compromise development and maturation. This is most prevalent in older women with DOR on drugs and/or stimulation protocols that increase LH-induced ovarian testosterone production. Examples include the use of clomiphene or Letrozole, “flare” agonist (e.g. Lupron, Buserelin) protocols, supplementation with hCG or testosterone during ovarian stimulation or over-dosage with LH/hCG containing gonadotropins (e.g. Menopur.) In my opinion, for women with DOR, a long pituitary down regulation protocol, coming off a birth control pill or off a natural cycle, with subsequent conversion to an antagonist (Ganirelix/Orgalutron/Cetrotide) at the onset of menstruation, followed by an FSH-recombinant stimulation and 10,000U hCG (Pregnyl/Profasi/Novarel) or 500mcg Ovidrel “trigger”, is preferred.

And, for women at high risk of developing severe ovarian hyperstimulation syndrome-OHSS (e.g. those with PCOS and women with hypogonadotropic ovulation dysfunction), I argue against cutting the period of ovarian stimulation short in order to arrest the hyperstimulation process, use of a lower “trigger “dosage of hCG or the using of an agonist (Lupron/Buserelin) “trigger”. Instead, I recommend use of a low-gonadotropin, long pituitary agonist down-regulation protocol combined selectively with “prolonged coasting.” In my opinion, use of the former, while capable of reducing OHSS-related maternal complications, does so at the expense of egg maturation, while the latter protects against OHSS while (provided it is implemented correctly) does so without prejudicing egg development.

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  • Kayla - April 10, 2017 reply

    Hello Dr. Sher,
    I was hoping you could explain the process of the egg/embryo during IVF? I have PCOS with periods ranging from 35-45 days apart. During my IVF cycle I had a mild case of OHSS, I was able to control it by drinking 120 oz of Gatorade/water, and increasing my sodium and protein and cutting out my sugars. I have been through one IVF cycle so far and with my egg retrieval, I produced 27 eggs good eggs (26-M1, 1-M2). On day 3 the RN called me to let me know that 8-9 eggs were maturing at the rate they wanted, and “several others” were a little ahead. On day 5 for transfer we went into the office and were told that only 1 egg made it to blastocyst phase. On day 6 we were told one more made it to blastocyst phase and was “fair” quality. So they froze it. From what I have been reading it is normal for about 30% of eggs to reach blastocyst phase. Is there any explainable reason why, out of 27 eggs, only 2 made it? This makes me so nervous to try again. Is there anything I or my spouse can do to increase success? Thank you for any advice.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 10, 2017 reply

    In my opinion, this is often a function of the protocol used for ovarian stimulation and the method and timing of the “trigger” in women who are at risk of developing OHSS (typically women with PCOS are so at risk)….see below.

    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
    • Taking A Fresh Look at Ovarian Hyperstimulation Syndrome (OHSS), its Presentation, Prevention and Management
    • Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
    • Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
    • “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
    • The “Lupron Trigger” to Prevent Severe OHSS: What are the Pro’s and Con’s?

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Alert ! - Dr. Sher will not have access to the internet, and will therefore be out of reach, from June 5 until June 25. Please re-submit this comment after that date. Until then, please explore the Sher IVF website and his Facebook videos archived on his page.

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