New approach to reproductive aging

It is common knowledge that a female’s fertility declines due to the decline in oocytes quality as a part of the normal aging process. Term maturation theory provides an approach for physicians to improve it. 

Chromosomal errors as a part of metabolic incompetence 

We do know that chromosomal errors are a chief, objective manifestation of oocytes aging. The evidence that women of advanced reproductive age have an increasingly high proportion of chromosomally abnormal oocytes is very strong and non-controversial. However, we do not know why this is the case. The “why” here is very important. It is crucial to recognize that ALL oocytes in older patients remain chromosomally normal until ovulation is triggered.

One of the generally accepted theories for chromosomal errors postulates that chromosomes of the oocyte at the germinal vesicle stage, particularly their so-called telomeres, become damaged by free radicals. This leads to chromosomal errors in oocytes, which persist after fertilization resulting in chromosomally abnormal embryos, which usually produce a miscarriage.

Yet, there is an observation that strongly contradicts this idea. It is well known that ionizing radiation is one of the most powerful DNA damaging agents. It is far more powerful than free radicals. One would fully expect that if DNA damage plays a major role in female fertility, we would see a reduction in fertility rates after exposure to ionizing radiation, but surprisingly this has not been the case.  This calls for an alternative explanation.

Injection of the cytoplasm from donor oocytes into the germinal vesicle oocytes of women of advanced reproductive age improves the chance of pregnancy. In this case, the chromosomes remain the same, which means that the metabolic competence of the cytoplasm prevents chromosomal errors. 

Those metabolic problems may at least in part be due to the inability of the oocyte to reach its full developmental potential during the follicular phase, or, in other words, they are unable to reach term maturation.   

Indeed, as we can see from the table below, the duration of the follicular phase has a clear tendency to shorten with age and has a dramatic effect on fertility. (Note that the standard deviation for all age groups is rather large. This means that in each age group there are females with very different cycle durations. This may explain why some women remain fertile longer while others have lower fertility even at a young age).

This shortening corresponds to the age-related drop in fertility

An egg does not control the duration of the cycle and therefore cannot be responsible for this shortening. The duration of the cycle depends on how long the follicle can survive during the follicular cycle, which in its own term is determined by the ability of the ovarian cortex to accommodate the follicle’s expansion from about 3 mm to 25 mm. The ovarian cortex’s elasticity diminishes with age and so does its ability to accommodate the follicle’s growth. The diminished ability of the ovarian cortex to accommodate the follicle’s expansion is a well-known phenomenon in IVF manifesting as a “vanishing follicle.” It is considerably more prevalent in a woman of advanced reproductive age. Vanishing follicle simply means that the follicle seen at the previous ultrasound disappears due to “mechanical reasons.”  To be sure, the reasons may not be purely mechanical, but reflect general propendency to inflammation with age. We commonly know this is true for joints, but it is also true for all connective tissues. Whether the propensity to inflammation or the loss of ovarian cortex elasticity, the end result will be the same – premature (“pre-term”) ovulation, before oocyte’s term maturation. Another age-related “hazard” is an elevated level of starting (baseline) FSH, which would tend to accelerate the pace of follicle’s expansion. Thus, two age-related tendencies reduced elasticity of the ovarian cortex and elevated baseline FSH synergistically reduce the duration of the follicular phase, allocating less time to the oocyte to reach full competency.

This creates a possibility that the reduction of fertility seen in many women of advanced reproductive age is not entirely due to the intrinsic problem with their oocytes. Instead, it may at least partially be due to the inability of a normal oocyte to reach developmental competency (term maturation). While we cannot improve  elasticity of the ovarian cortex, we can reduce the amount of FSH in circulation and also reduce inflammation that accompanies the final stages of the follicle’s expansion thereby delaying its disintegration and enabling the oocyte to reach term maturation.

Another point to consider. As we age, many metabolic processes slow down. Therefore, (I am going out on a limb here), as a woman gets older her oocytes may actually need more time to reach full developmental potential. This means, that if it takes an oocytes 16.5 days at 20 years of age, it may take 18 days at 40 years of age

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