The “Biological Clock” and How it Should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.

Dr. Geoffrey Sher - January 18, 2016
The “Biological Clock” and How it Should Influence   the Selection and Design of Ovarian Stimulation  Protocols for IVF.

It is inevitable reality that all women will at some point or another, experience a progressive decline in their reproductive potential. This occurs as their ovarian egg population falls below a theoretical threshold. Ultimately once it is all but depleted, a total cessation of ovulation and menstruation (the menopause) ensues making the chance of having a baby with own eggs virtually impossible. This decline in so called “ovarian reserve” usually starts when the women reaches her mid-thirties, accelerates she approaches and enters her 40’s, ending with the onset of menopause. In a small but significant percentage of women, the process of diminishing ovarian reserve (DOR) commences much earlier, often leading to premature menopause occurring, before the age of 40 years. Ultimately however, it is not only ovarian reserve that affects the woman’s reproductive potential, but also the “competency” of her eggs (i.e. their potential, upon fertilization to propagate embryos that have the potential to develop into normal offspring) The term “biological clock” refers to the impact of both these factors on  the woman’s reproductive potential.

  1. “Ovarian Reserve”: The number of eggs available in a woman’s ovaries at any given time is referred to as the woman’s “ovarian reserve”. All women are born with all the eggs that will be 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 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 varies), ovarian reserve starts diminishing (DOR) that is characterized by an increase in the release by the pituitary gland of both FSH and LH ,in  a fruitless effort to prompt the ovaries to produce more eggs. Concomitantly blood Anti-Mullerian Hormone (AMH) levels begin to decline.
  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.
    1. 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.
    2. 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”. It is my considered opinion, especially when comes to older women and women with DOR that, the dosage of drugs (e.g. Menopur) or ovarian stimulation protocols that deliver too much LH (or hCG)  or stimulate over-production of LH by the pituitary gland (agonist/Lupron “flare” protocols) , should best be limited in women undergoing IVF because excessive LH/hCG activity induces excessive ovarian testosterone production which can and does compromise egg competency. This is particularly advised in older women and those who have DOR where too much LH-induced testosterone activity often already exists. There are also certain medications that provoke overproduction of pituitary LH (e.g.  clomiphene citrate, and Letrozole/Femara). Accordingly, for the same reason, these too are best limited in women undergoing IVF …most particularly in older women and women who have DOR.  Instead, long protocols that down-regulate LH and include delivery of predominantly purified FSH, should in my opinion be used preferentially.

The role of embryo banking: The introduction of embryo karyotyping (using PGS) has opened the door to older women as well as those with DOR accumulating numerous competent (PGS-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 such women whose “biological clocks” are fast running out of time, the only realistic option of still having a baby with their own eggs. For those who have very severe DOR , Egg Donation-IVF represents the best recourse


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