The Biological Clock

Summary

There has been considerable discussion about the so-called “ biological clock,” and its affect on female reproductive capacity. Indeed, some recent research theorizes that the quantity of a woman's eggs may deteriorate much earlier in her life than previously thought. However, as a result of research here at CHR, we believe the implications of the maternity-related biological clock are overstated and overlook the main issue. Our work shows that the most important aspect of female fertility is not the quantity of her eggs, but the quality. In addition, our research on ovarian aging involving DHEA has shown that though the number of eggs naturally diminishes, if the quality of the remaining eggs can be maintained, pregnancy remains possible longer in life than some of the recent pessimistic claims might suggest.

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Unwinding the Biological Clock Issue

It's well known that follicle/egg numbers in human ovaries decline quite rapidly. Indeed, the story could be extended to the female embryo prior to birth because it is actually during that intrauterine time that most follicles/eggs are lost. Follicle/egg loss is, thus, a permanent feature from the time when follicle/eggs are created in embryonic life. The younger the female (including intrauterine life) the quicker and the larger the loss; the older she gets, the smaller and slower the deterioration.

CHR research and the Biological Clock

Investigators at CHR have in recent years done extensive work on the concept of ovarian reserve (OR). OR is an acronym, widely used to describe the remaining fertility capacity of a woman’s ovaries. It, of course, mostly depends on how many follicles/eggs are left. It, therefore, has been known for many years that a woman’s OR declines as she ages because her follicle/egg numbers decline.

OR is, however, not only defined by smaller follicle/egg numbers; as women age their follicle/egg quality also deteriorates. Women, thus, face a double insult on their reproductive integrity as they age.

Investigators at CHR recently discovered that the decline in follicle/egg numbers is not the same in all women. It appears to differ, depending on how many triple nucleotide (CGG) repeats a woman carrier on her FMR1 (fragile X) gene. The normal number of such repeats in regards to OR appears to lie in the 26-32 range. Counts below or above negatively affect OR especially at younger ages, though, paradoxically, may actually improve OR at more advanced ages (Gleicher et al, RBMOnline; In press). 

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Focus on Biological Quality, not Quantity

It, therefore, would be a mistake to assume that all women age their ovaries in exactly the same way. There can be distinct differences and, indeed, approximately 10% of all women are believed to age their ovaries earlier that most other women.

CHR investigators recently also discovered that, while it does not appear possible to affect the decline in follicle/egg numbers with advancing female age, it may be possible to beneficially affect follicle/egg quality. They reached this conclusion after observing unusually low miscarriage rates in women with extremely poor OR who conceived after dehydroepiandrosterone (DHEA) supplementation.

Such low miscarriage rates suggest a positive effect of DHEA on ploidy (chromosomal abnormalities) and, therefore on follicle/egg quality. They argued that, since it appears unlikely that an already bad egg can be “‘rejuvenated,” current thinking about how eggs age within the ovary may have to be reconsidered: Instead, as is currently believed, aging eggs with advancing female age, aging ovarian environments appear the culprits that cause egg damage and increasing chromosomal abnormalities.

Under this new concept, the egg within un-recruited follicles does NOT age as women grow older. Once this egg is recruited into so-called folliculogenesis (a ca. 4.5 month long journey of follicular/egg maturation), this egg, however, enters at different female ages different quality of ovarian environments: the older the woman, the poorer. It is then this poor environment that negatively influences folliculogenesis and egg maturation, leading to poorer quality eggs (and embryos).

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DHEA and recalibrating the Biological Clock

If confirmed, this CHR-developed concept would be revolutionary because it would suggest that, even though older women, of course, have much fewer follicles/eggs than younger women, those few they have could be matured through pharmacologically improved ovarian environments. Their maturing eggs would, therefore, be fewer but would lack the second insult of poor quality. As a consequence, older women would greatly improve their reproductive chances, even with fewer follicles and eggs available for folliculogenesis.

Conclusions from all of this are that numbers are important but quality always exceeds quantity in importance. If CHR investigators are correct in the interpretation of their DHEA data, then DHEA represents a first medication that improves ovarian environments in women with abnormal OR. Many other such medications can be expected in the future, giving older women with diminished OR a very promising future of expanded reproductive life spans.     

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