IVF and the “Ticking Biological Clock”: Can it be tempered?
The term “biological clock” is often used to quantify the progressive inevitable decline in reproductive potential that occurs over time in all women. The “clock” usually starts to accelerate after age 35, and then picks up speed over time. In most cases, time will run out completely with the menopause, somewhere between ages 40 and 55 years. In some cases the process begins at a much younger age.
This article will attempt to demystify the term “biological clock” by explaining its components, defining its effects on reproductive performance and by addressing ways in which fertility treatment might be altered or modified to temper its devastating effects.
1. The concept of the ovarian reserve: The cumulative number of eggs available in a woman’s ovaries at any given time constitutes her “ovarian reserve”. All women are born with all the eggs available to them through their lifetime. The majority of these eggs are lost between birth and puberty. The remainder will be used up progressively. Once they ‘run out” the woman stops ovulating and menstruating…i.e., the menopause has been reached. The number of eggs available from the onset of menses (menarche) to menopause differs from woman to woman and is genetically determined. Once the total number of eggs falls below a certain threshold (which also can vary) the woman is on course for developing diminished ovarian reserve (DOR) which will be characterized by her pituitary gland releasing more FSH and LH (in a fruitless effort to prompt the ovaries to produce more eggs). Concomitantly blood Anti-Mullerian Hormone (AMH) levels and Inhibin-B levels begin to decline.
Most women will start to manifest with DOR when they reach their late thirties or early forties. However, in some cases DOR occurs at a much younger or older age. DOR heralds the onset of a 6-10 year period, referred to as the “climacteric” which often begins with dysfunctional ovulation and growing resistance to fertility drugs, progresses to premenopausal symptoms such as hot flashes and failing menstruation, and culminates with total cessation of ovulation and menstruation…the menopause.
2. “Egg competency”: It is primarily the egg, rather than the sperm that determines the ultimate ability of an embryo to propagate a viable baby. To be “competent”, an embryo must have all 46 chromosomes intact (i.e. it must be euploid). Only a mature (M2) egg that has its full contingency of 23 chromosomes (i.e. is “competent”) has the potential, (upon being successfully fertilized) to propagate a “competent” embryo.
Two factors affect egg competency: a) Age and, b) Ovarian hormonal environment during egg development.
a. Age: Up to age 30Y, roughly one in two M2 eggs are likely to be chromosomally normal; 1 in 6 by age 40; 1 in 10 by age 43Y and about 1 in 20 by age 45. “Embryo competency” follows the same age-related decline. This serves to explain the decreasing fertility, rising miscarriage rates and increasing chromosomal birth defects that occur with advancing maternal age.
b. Ovarian hormonal environment: As a woman get older and/or as her ovarian reserve declines, her pituitary gland starts producing luteinizing hormone (LH) in increasing amounts and/or biopotency. This chronic increase in LH activity can cause her ovaries to over-produce male hormones (predominantly testosterone). While these hormones are essential for follicle production of estrogen and for egg development, excessive testosterone compromises egg development and increases the likelihood of chromosomal numerical irregularities (aneuploidy) and aneuploid eggs cannot propagate “competent embryos”.
Taking the above two factors into consideration, it is my opinion that (especially when comes to older women and women with DOR), the use of drugs or ovarian stimulation protocols that deliver or stimulate the over-production of LH, should best be avoided. Examples include the use of clomiphene citrate, letrozole and certain menotropins (e.g. Menopur). Instead, long protocols that down-regulate LH and include delivery of predominantly purified FSH, should in my opinion be used preferentially.
Embryo banking…the last option before resorting to Egg Donation: The introduction of full embryo karyotyping (using CGH and other testing methods) has opened the door to older women as well as those with DOR accumulating numerous competent (CGH-normal) embryos over multiple IVF cycles of stimulation. Since such euploid embryos (regardless of their often having been derived from older women), usually display comparable viability to those derived from younger counterparts. The process, referred to as Embryo Banking offers women whose “biological clocks” are fast running out of time, the only realistic option of still having a baby with their own eggs. Those for whom the Biological Clock has run out completely, can turn to Egg Donation-IVF as their only remaining option.
It so happens that in most cases, advancing age and DOR run parallel with one another. However, as stated above, sometimes DOR occurs in young women. When this happens, provided that the protocol for ovarian stimulation can be individualized to protect egg development, “embryo competency” should not be significantly compromised. True, older women with DOR who, because of age, also have declining “egg competency” do not only have to deal with the likelihood of having fewer “euploid” eggs available but also with the likelihood of a much smaller percentage of their eggs being “competent”. Thus, in this respect, both these negative variables will interact. At the same time it should be borne in mind that in large part, DOR and Egg Competency are independent variables and that the one ordinarily should not affect the other directly.