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”.