This is the final post in a series of answers to 10 frequently asked questions about IVF.

#10 Am I too old to use my own eggs? Do I need an egg donor?

Women are born with all the eggs they will ever have. After menarche (the earliest onset of menstruation) a monthly process commences whereby a number of eggs are used up each month. This process continues until the number of eggs remaining in the woman’s ovaries falls below a certain threshold beyond which there is a progressive diminution in “ovarian reserve,”ovarian hormonal activity often becomes erratic and dysfunctional and the woman develops diminishing ovarian reserve (DOR) during which time she becomes progressively more resistant to ovarian stimulation with fertility drugs. In such cases the dosage of fertility drugs needed to achieve follicle/egg development progressively increases until the point is reached where she can no longer respond regardless of the dosage of FSH that is administered. This 6-8 year phase of the woman’s reproductive life is referred to as the “climacteric”.

The onset of the climacteric is heralded by gradually increasing blood concentrations of FSH on the 3rd day of a spontaneous menstrual cycle and a decline in antimullerian hormone (AMH) and inhibin B levels. This continues for a number of years until the vast majority of remaining eggs have been used up, at which time ovulation and menstruation both cease and…the “menopause” has arrived. Symptoms such as hot flashes, mood changes, and vaginal dryness producing local discomfort with intercourse usually signal the imminence of the menopause.

The timing of the onset and the duration of the climacteric both vary from person to person. Genetic factors, exposure to environmental toxins and radiation, disease, drugs and pelvic disease associated with severe periovarian adhesions that compromise blood flow to the ovaries, can all influence the timing of the onset of both the climacteric and the menopause. Most American women will enter the climacteric in their early to mid forties and go into menopause around 45-52yrs. However, some women enter the climacteric much earlier on.

Reduced ovarian responsiveness to fertility drugs is usually the direct consequence of a decline in ovarian function brought about by the onset of the climacteric and pending menopause. Egg quality, on the other hand is directly related to the woman’s age. This is how it works:

Upon undergoing LH (or hCG)-induced maturational division (meiosis) the egg’s chromosome number is supposed to halve from 46 to 23 during the 24-42 hour period preceding ovulation (or egg retrieval in IVF). In humans, this process is rather imperfect, with most mature eggs ending up having more or less than the required 23 chromosomes following meiosis. A cell that has an irregular number of chromosomes is referred to as “aneuploid.” The sperm also undergoes meiosis and in the process divides in two. The objective is for each mature sperm to contain 23 chromosomes so that upon the egg and sperm combining at fertilization the resulting embryo will be euploid (i.e. contain precisely 46 chromosomes-the normal human quota). It is much more the egg than the sperm that ultimately will determine the chromosomal integrity of the embryo.

Even in younger women (under 35 years) only about 40% of eggs turn out to be euploid (i.e. have a normal quota of 23 chromosomes). As such, even in young women (under 35 years of age) 3 out of 5 mature eggs are in fact aneuploid and this increases progressively with advancing years, such that by the mid forties, at least 9 out of 10 eggs are aneuploid. Since aneuploid eggs invariably propagate aneuploid embryos, it follows that with every advancing year it becomes progressively more likely that a woman’s embryos will likewise be aneuploid(have more or less than 46 chromosomes) and aneuploid embryos are the main cause of Reproductive Failure ( infertility, very early pregnancy loss, or chromosomal birth defects such as Down’s syndrome). This also serves to explain why treatment of infertility (regardless of the chosen method) becomes progressively less successful with advancing maternal age and why miscarriages and conditions such as Down’s syndrome increase in prevalence with advancing age . Thus it is the age of the woman rather than diminished ovarian reserve (DOR) that results in an increased incidence of embryo “incompetence” (failure top propagate a normal baby) and this is primarily attributable to egg aneuploidy.

Since the onset of the climacteric with its accompanying DOR usually (but not always) coincides with the woman being over 40 years, there is an erroneous tendency to attribute poor egg/embryo quality to DOR with rising blood levels of FSH and/or declining AMH/Inhibin B. The truth is that advancing maternal age, rather than DOR, is the reason for a progressive increase in egg aneuploidy and a decline in embryo “competence”(the ability to result in a normal pregnancy).

Blood FSH and AMH/Inhibin-B all measure ovarian reserve, which in turn equates with the woman’s potential to respond to controlled ovarian stimulation (COS). These parameters od ovarian reserve roughly correlate with the number of follicles/eggs likely to be available at egg retrieval (ER), but not with the quality/competence of the eggs. The main determinant of embryo competence due to aneuploidy is thus the age of the egg provider but this (especially in oldewr women and those with DOR can also be influenced by the COS protocol for ovarian stimulation. In fact each egg derived from a young woman with “premature” DOR, should have roughly the same likelihood of being chromosomally normal as for a woman who has normal ovarian reserve. The number of eggs harvested would however likely be lower. On the other hand, an older woman with DOR would likely yield both fewer eggs as well as a higher percentage that are aneuploid. Obviously, regardless of the age of the woman, the greater will be the number of eggs harvested at ER and the better the relative opportunity would be to find and select competent embryos for embryo transfer (ET).

The ovaries and developing eggs of women with DOR (regardless of her age) are highly susceptible to the adverse influence 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 (http://haveababy.com/fertility-information/ivf-authority/ivf-ovarian-stimulation-gnrh/) 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 or individualized protocols of ovarian stimulation are less likely to make competent eggs/embryos.

While NOTHING can be done to lower the incidence of age-related egg aneuploidy, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocol of ovarian stimulation used. In my opinion the following ovarian stimulation protocols are best avoided in women with diminished ovarian reserve because they either contribute towards a higher LH/testosterone ovarian environment or do nothing to regulate these hormones prior to or during ovarian stimulation:

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
d) Clomiphene citrate or Letrozole.

Some years back, our fertility clinic (Sher Institute) was the first to introduce agonist/antagonist conversion protocols (A/ACP) which we have found to 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.

SIRM was the first to introduce Comparative Genomic Hybridization (CGH) into the clinical setting. This game-changing genetic technology, for the first time permited identification of all the chromosomes in the egg and embryo. As a result we can now far better identify competent (chromosomally normal) 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.

Egg Donation
For women whose advancing age and/or ovarian resistance make having a baby with their own eggs unappealing or unlikely, ovum donation (using eggs from a young donor – usually compatible and anonymous) is a highly successful option. Here, outcome is unaffected by the age of the intended mother – assuming she is healthy.

Embryo Banking
We recently introduced yet another option for older women and those with DOR who (regardless of their age) wish to minimize the relentless effect of the biological clock. It is called “Embryo Banking.” This option allows such women to undergo several IVF procedures in relatively quick succession and in the process freeze/bank (vitrify) all blastocysts derived from CGH-normal (euploid) embryos for future dispensation, rather than having them transferred fresh to the uterus. Such embryo “stockpiling” can literally stop the biological clock in its tracks since it provides women who are running out of time to prolong their reproductive potential . As such Embryo Banking could help offset progressively declining egg/embryo “competency” over time.

The concept of Embryo Banking/stockpiling would not have been feasible even 5 years ago, since it was not until quite recently that we became able to reliably identify chromosomally normal (“competent”) embryos for selective banking. Nor was it then possible until the advent of ultrarapid embryo freezing (vitrification) to prevent freezing from severely damaging up to 50% of frozen embryos.

Today, through the adaptation of Comparative Genomic Hybridization (CGH) technology to egg and/or embryo selection, we are able to much better identify “competent” embryos and thus select these for banking and stockpiling.

In conclusion: Older women (over 39 years) and/or women with DOR (regardless of their age) wanting to have babies using their own eggs cannot afford to procrastinate when it comes to deciding on a definitive strategy by which to achieve their goal. They simply do not have the time to so indulge. However, before proceeding, it is imperative that such women first ask themselves one very important question, namely:

“Do I want to have just one child, or do I want more than one?”

If the answer is that they only wish to have one baby, then they need not consider Embryo Banking with CGH. However, if the answer that they would like to have more than one child, then they should seriously consider this option. Think of it this way….if a woman who is running out of time conceive following IVF, it would likely be a few years later by the time she would be ready to try IVF again and by this time, her age and/or DOR would likely severely impede her chance of success. For such women therefore, banking CGH-normal (competent) embryos over several IVF cycles (conducted in relatively close succession) before undergoing ET could permit the storage of enough “competent” embryos so as top to make having another baby possible.

For those women who are willing to go directly to egg donation, there is a lack of urgency as it relates to the biological clock. This affords them the latitude of time such that there would be no rush …they could take their time!