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

Dr. Geoffrey Sher - April 10, 2017
Egg Maturation in IVF: How Egg “Immaturity,” “Post-maturity,” and “Dysmaturity” Influence IVF Outcome.

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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