Cutting-Edge Exploration of Ovarian Reserve at CHR
What is ovarian reserve?
Ovarian reserve is a measure of how well a woman's ovaries are still working. A principal function of the ovaries is to produce mature eggs (oocytes) that become embryos when fertilized with sperm. The ovarian reserve, therefore, describes approximately how many viable eggs are still left in the ovaries of a woman. This is why ovarian reserve is sometimes called oocyte reserve or egg reserve.
How does ovarian reserve change with age?
The ovarian reserve declines with age. This decline culminates in menopause, when only a very small number of eggs are left in the ovary. Current dogma holds that women are born with a finite number of eggs.
|The figure above describes the maturation process (folliculogenesis) that eggs go through. Women are born with a finite number of eggs in a dormant state called "primordial follicles." Every month, hundreds or thousands of eggs are recruited into folliculogenesis, with usually only one of them reaching full maturity. The mature egg is released in ovulation, while others become apoptotic (degenerate). As women age, the pool of primordial follicles diminish, reflected by "diminished ovarian reserve."|
At present, the general understanding is that this finite pool of follicles and eggs is maintained in the capsule of the ovary in a very immature state, the so-called primordial follicle. From this pool of immature eggs, hundreds to thousands are recruited into the maturation process each month. Only one of these recruited eggs, however, reaches full maturity and is released from the ovarian follicle during ovulation each month after a journey of maturation. This maturation process can take from months to almost a full year. The rest of follicles and eggs degenerate (die off) during the various stages of the maturation process, called folliculogenesis, with the debris being removed in a process called apoptosis.
This process of folliculogenesis "uses up" a women's follicle pool as she ages. Consequently, ovarian reserve declines with age, as schematically shown in the figure above.
However, some investigators have recently started to question this dogma: A study by Harvard investigators and scientists from Japan, supposedly demonstrating that stem cells in mouse and human ovaries can be converted into follicle (and eggs), support the possibility that, at least a small number of follicle/eggs may be formed after birth. This, however, remains to be confirmed.
Current widely held understanding also holds that even the yet-to-be-recruited, immature eggs deteriorate in quality as women age. This "aging" of eggs is, therefore, believed to be the reason why women with diminished ovarian reserve produce not only fewer eggs, but also poor quality eggs. As women age, this declining egg quality is believed to lead to more chromosomal abnormalities in embryos and higher miscarriage rates.
CHR's research into ovarian reserve and ovarian aging
New research at CHR also challenges this dogma. Here is why:
- CHR has, for a number of years now, been supplementing women with diminished ovarian reserve with the mild androgen dehydroepiandrosterone (DHEA). As reported in a number of peer-reviewed CHR publications, DHEA "rejuvenates" ovarian function in these women to a degree, allowing them to produce more, and better-quality eggs. The ultimate results are higher IVF pregnancy rates and lower miscarriage rates, as demonstrated by our excellent IVF pregnancy rates even in women with significantly diminished ovarian reserve.
- If a pharmacological agent like DHEA can have such an effect on ovarian function, the logical conclusion has to be that immature eggs in primordial follicles, very likely, do not age after all, as women advance in their ages. If eggs, indeed, were to deteriorate with advancing female age, they would incur irreversible damages. It appears very unlikely that DHEA supplementation can reverse already existing damage in "aged" eggs, which would be the only reasonable explanation for above described improvements in ovarian performance after DHEA supplementation.
- This means that there needs to be an alternative explanation for how DHEA can achieve these benefits, and the only such alternative explanation is that current assumptions about aging of immature eggs (oocytes) have to be reconsidered.
- Indeed, the only model of ovarian reserve compatible with above noted beneficial effects of DHEA is a radical change of concept, which no longer believes that eggs age as women grow older, but that the ovarian environment, in which eggs mature during folliculogenesis, ages.
- Under such a concept, primordial follicles, with their very immature eggs, exist in a state of "suspended animation," which can be equated to cryopreserved (frozen) eggs/embryos, with almost no need for energy and, therefore, not exposed to the potential damages of advancing age. Once recruited into follicle maturation, these very immature follicles and eggs, however, now enter an ovarian environment that does change with advancing female age.
- Immature follicles, matured in "older" environments face more adverse outcomes—for example, more aneuploidy (chromosomal abnormalities). It, therefore, is the age of the ovarian environment that matters, and not the age of the follicle/egg.
- On first glance there may appear no obvious difference between these two ovarian aging concepts, but there is one very important difference: As already noted above, it appears extremely unlikely that DHEA (or other androgenic hormones) would be able to reverse already existing damage in eggs. In contrast, it, indeed, appears very likely that supplementation with DHEA (and other androgens) can restore declining androgen levels within the ovarian environment, when it is known that these levels significantly decline with advancing female age, and that androgens are of crucial importance for normal follicle growth in the early stages.
|The figure illustrates the early stages of follicle maturation, when eggs respond to androgens, including DHEA, supplementation. Typically, these are the stages of follicle maturation that are neglected in fertility treatment setting. A vast majority of IVF centers only focus on a few weeks during ovarian stimulation.|
CHR's work with DHEA (and other androgen) supplementation has, to a degree, revolutionized the clinical treatment of women with low ovarian reserve. It now appears that this work will also revolutionize our understanding of ovarian aging. Aside from DHEA (and other androgens), other pharmaceutical intervention may also be able to further improve the ovarian environment in older women, and, therefore, further improve pregnancy chances at older ages.
Can women with low ovarian reserve conceive with treatment?
As the "fertility center of last resort" for women from all over the world, we see women every day who were told that their ovarian reserve is so low that their only chance of pregnancy is through egg donation. With a combination of DHEA (or other androgen) supplementation, individualized ovarian stimulation protocols and careful management of associated conditions, approximately one-third of such women still end up conceiving with use of their own eggs at CHR. We here at CHR are known "to fight for every egg and embryo!"
This, of course, still leaves two-third of patients who, indeed, do need donor eggs; but for that one-third of women, the difference in outcome makes quite a difference! And for those who really have to resort to donor eggs, CHR, likely, offers the largest and most divers pool of carefully selected egg donors anywhere in the world. These patients, therefore, instantly, usually select a donor, and experience absolutely no treatment delays.
If you believe that you may benefit from CHR's special expertise and services described here, please contact us to get started.
Written by Norbert Gleicher, MD
Last Updated: January 16, 2013