Fertility Topics Explained from the Experts at SFS
It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy baby. When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 1 out of 2 eggs are chromosomally numerically normal (euploid). The remained have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are competent, and by the mid-forties, less 8 to 9 out of 10 are aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploid and an aneuploid embryo cannot propagate a normal pregnancy. Within hours of the spontaneous pre-ovulatory luteinizing hormone (LH) surge, and also following administration of the human chorionic gonadotropin (hCG) "trigger" shot (given to induce ovulation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining (now redundant) 23are expelled, enveloped by a thin membrane. This small structure comes to lie immediately below the "shell" of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The spermatozoon, in the process of its maturation also undergoes meiosis at which time it too reduces its chromosomes by half. Thus in the process of fertilization the sperm divides into two separate functional gametes, each containing 23 chromosomes such that with subsequent fertilization, the 23 chromosomes in the egg, fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo that has 46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners. For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of developing into healthy babies. While embryo "incompetence" can result from either egg or sperm aneuploidy, it 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. While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is rate-limiting factor in human reproduction. It is causal in most cases of “failed implantation” which in turn is responsible for most cases of failed IVF. It causes early miscarriages and is responsible for many chromosomal birth defects such as X-monosomy and Down’s syndrome. . 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 certain 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. Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo "incompetence" due to aneuploidy 2. DOR: 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. Selection of the ideal protocol for controlled ovarian stimulation: While NOTHING can be done to lower the incidence of age related aneuploidy, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocols of ovarian stimulation used.
When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In some cases where the DOR is regarded as severe, I also augment the process with estrogen priming, preferring twice weekly intramuscular administration of estradiol valerate (Delestrogen), starting with the commencement of antagonist injection and continuing for 1 week before commencing gonadotropins and continued until the hCG “trigger. I further recommend that such women be offered access to preimplantation genetic testing (PGT) for4 embryo selection and in some cases, for embryo banking (stockpiling). This is followed in a later hormone replacement cycle with the selective transfer of up to two (2) PGT-normal, euploid blastocysts. In this way we are able to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” , significantly enhancing the opportunity to achieve a viable pregnancy
The introduction of preimplantation genetic testing (PGT) for the first time permits identification of all the chromosomes in the egg and embryo such that we can now far better identify "competent" (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process. This additional tool has better equipped us to manage cases with DOR. In my opinion, next generation gene sequencing (NGS), currently represents the most reliable method for performing PGT.
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