The spermatozoon, in the process of its maturation also undergoes meiosis at which time it too reduces its chromosomes by half but instead of discarding 23 chromosomes, it simple diveides into two . Thus in the process of fertilization each immature spermatozoon with 46 chromosomes propagates two mature spermatazoa, each containing 23 chromosomes. The subsequent fertilization of a 23 chromosome-containing egg, by a mature sperm with 23 chromosomes propagates an embryo that has 46 chromosomes (the normal human genome). Thus for an embryo to have exactly 46 chromosomes (the euploid number) and thus be "competent(have the potential to develop into a baby), both the mature egg and mature fertilizing spermatozoon must each contain exactly 23 chromosomes.
Those embryos that bhave an irregular number of chromosomes (i.e. aneuploid) are incapable of developing into healthy babies (“incompetent”). While embryo "incompetence" can result from either egg or sperm aneuploidy, it is 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.
Embryo aneuploidy is by far the most important rate-limiting factor in human reproduction and is the most common cause of “implantation dysfunction” and failed IVF, early miscarriages and many chromosomal birth defects such as X-monosomy and Down’s syndrome.
When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women, at best only 2 out of 5 eggs are chromosomally normal (euploid) and this decreases progressively with the advancing age. By age 35 years, only about 1 in 4 is competent, and by the mid forties only 10-15% are chromosomally normal.
The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy, and as stated, an aneuploid embryo cannot propagate a normal pregnancy. 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 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. It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood FSH/inhibin B or antimullerian hormone) that results in an increased incidence of egg/embryo "incompetence" due to aneuploidy
2. 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.
NOTHING can be done to lower the incidence of age related aneuploidy, however, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocols of ovarian stimulation used. In my opinion the following ovarian stimulation protocols are best avoided in women with diminished ovarian reserve:
a) Microdose agonist (e.g. Lupron) flare protocols
b) High doses of LH/hCG-containing fertility drugs such as Repronex or Menopur. c) Traditional GnRH antagonist protocols protocols
d) Clomiphene citrate or Letrozole.
3. In 2007, SIRM introduced agonist/antagonist conversion protocols (A/ACP) that optimize the number and quality of oocytes made available for IVF/ICSI and optimize IVF pregnancy rates in women with diminished ovarian reserve and in older women. 4. With the introduction of Comparative Genomic Hybridization (CGH) that for the first time permits identification of all the chromosomes in the egg and embryo we can now far better identify "competent" (euploid) embryos for selective transfer to the uterus, and thereby vastly improve the efficiency and success of the IVF process. This additional tool has better equipped us to manage cases with diminished ovarian reserve.
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