Aneuploidy Age and Ovarian Resistance

ANEUPLOIDY AGE AND OVARIAN RESISTANCE

Geoffrey Sher MD

Advancing age is associated with a progressive increasein the number of eggs (oocytes) that exhibit numerical chromosome abnormalities (aneuploidy. The fertilization of such aneuploid eggs, inevitably leads to the resulting embryo being aneuploid and incapable of spawning a normal conceptus. While the chromosome make-up of the egg plays a small role in the likelihood of embryo aneuploidy occurring, it is the egg that plays the dominant role, in fact, in >90%embryo aneuploidy is traceable to the egg.In most cases, microscopic morphologically defined “poor embryo quality” is synonymous with embryo aneuploidy and embryos that develop disproportionately slowly or too fast (i.e. less than 7 cells or >8cells within 72 hours of IVF/ICSI).

Embryo aneuploidy is by far the most important rate-limiting factor in human reproduction, being responsible for most cases of “implantation dysfunction” which in turn is responsible for failed IVF, chemical pregnancies and early miscarriages as well as for certain chromosomal birth defects such as X-Monosomy and Down’s syndrome.

With the spontaneous LH surge or following hCG trigger, there a rapid maturation of the egg (Meiosis) takes place so that by the time the egg ovulates (38-42 hours later}or is aspirated for IVF, its chromosomes have divided in half (from 46 to 23). One half of the chromosomes (23), the haploid number remaining inside of the egg with the remaining 23 being expelled to the outside of the egg immediately underneath the egg envelopment (Zona Pellucida) as a polar body. With fertilization, thehaploid number of chromosomes left inside the egg substance combines with a likewise haploid number of sperm chromosomes. (The sperm having previously divided its 46 chromosomes in half , so as to form two mature haploid sperm each with 23 chromosomes)

Even in young women about65% of eggs are aneuploid. The incidence increases with advancing age so that bat 40-42 years, the incidence is about 80%, rising to >90% at 45.

While age is certainly the most important factor determining the incidence of egg/embryo aneuploidy, it is important to recognize that this incidence can rise well above the age-related threshold during controlled ovarian hyperstimulation (COH) with fertility drugs, , especially in older women and women who have “diminished ovarian reserve” when “recipe type protocols for COH are used. This is most likely to occur when the ovaries are exposed to “too much LH”, e.g with microdose agonist (Lupron) flare protocols, high dose LH is administered (such as with Repronex or Menopur) or late antagonist (Cetrorelix/Antagon/Orgalutron/Ganirelix) protocols are used.

While one can do NOTHING to lower the incidence of age related aneuploidy, it is possible to avoid a further increment in egg/embryo aneuploidy through individualizing the protocols of ovarian stimulation used.

“A t SIRM we have developed and customized ovarian stimulation protocols that optimize the number and quality of oocytes available for IVF/ICSI, maximizing pregnancy rates with IVF performed in “poor responders”.