The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
In this post, we’ll discuss age related factors that contribute to egg quality. Tomorrow’s post will discuss ovarian stimulation related factors. Age & Egg/Embryo Quality: A woman is born with all the eggs she will ever have.
After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise.... at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing, is the detection of a blood FSH level above 9.0 MIU/ml (in association an estradiol level of <70pg/ml) as measured on the 2nd or 3rd day of the menstrual cycle. While the age of onset of both the start of the climacteric as well as the advent of menopause is genetically determined (this may vary from woman to woman,) other factors, such as exposure to radiation, systemic and pelvic adhesive disease, ovarian trauma or surgical removal of the ovaries can hasten the onset of both events. Most American women will enter the climacteric in their early to mid-forties and go into menopause around 45-55 years of age. The quality of an egg is largely defined by its chromosomal configuration.
Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature spermatazoon ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. With ovulation induction using fertility drugs, the administration of hCG (the hCG "trigger") mimics the LH surge. A "competent" mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is "competent" to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, "competent” embryo. Thus egg/embryo aneuploidy ("incompetence") is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down's syndrome). While most aneuploid ("incompetent") embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down's syndrome).
Up until a woman reaches her mid thirties, only about 2 in 5 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their
Microscopic Grade alone. Even when turning to conventional chromosomal evaluation of embryos by way of Preimplantation Genetic Diagnosis (PGD) using fluorescence in-situ hybridization (FISH) it remains impossible to differentiate between "competent" and "incompetent" (euploid and aneuploid) embryos reliably. This is because at best, PGD/FISH can only access 12 of the 23 pairs of chromosomes. Thus, even when an embryo tests FISH-“normal,” there remains about a 40%-50% chance that the diagnosis is erroneous. The recent introduction of comparative genomic hybridization (CGH) could change all this. By allowing access to all the chromosomes CGH permits a much more reliable assessment of embryo "competence”. Our research has shown that the transfer of even a single CGH-normal embryo yields better than a 60% chance of a healthy baby. This represents a several-fold improvement over prior methodologies.
The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.
It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality ("incompetence") often occurs in women who at the same time, because of the advent of the climacteric also have elevated blood FSH levels. But it is not the elevation in FSH that causes embryo "incompetence". Rather it is the effect of advancing age (the "biological clock") resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older "wear and tear" on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.
Stay tuned for tomorrow’s post on factors relating to the effect of ovarian stimulation with fertility drugs on egg/embryo quality.
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