Female age and fertility: Why age is the most important pregnancy predictor

Advancing age usually means declining chances of pregnancy, but too many women are pushed into egg donation prematurely

Female age, fertility and egg quantity/quality

The honest truth is that nobody fully understands why age is by far the most important predictor of pregnancy success, whether women attempt pregnancies with or without medical help, but there can be no doubt that female age plays a very essential role that goes far beyond the fact that women are born with, likely all of their eggs, and constantly lose some when they are recruited from their resting stage (in primordial follicles) into a maturation process called folliculogenesis that lasts up to three to four months. As women age, their ovaries, therefore, contain fewer and fewer eggs. As a consequence, the number of eggs recruited into maturation declines and the number of eggs retrieved in IVF cycles diminishes. Declining egg numbers, therefore, unquestionably, are one factor that contributes to declining fertility.

age-related decline in ovarian reserve

That, however, is not the only and, likely, not even the principal, reason. In parallel with declining numbers, quality of eggs also declines. We know that because egg quality makes up roughly 95% of embryo quality, and the chance for an embryo to implant is radically age-dependent: An embryo produced from a 25-year old egg will, therefore, have a much higher implantation and pregnancy potential than an embryo made from a 35- or even 45-year-old egg. Though there are exceptions, the general rule, therefore, is that egg numbers and egg quality run in parallel.

Two ways egg quality declines with women’s age

CHR investigators, however, added some subtlety to this formula, when establishing what since has been called “CHR’s theory of ovarian aging,” which states that the ovarian aging process is not only the consequence of aging eggs while sitting in ovaries at resting stage, but also is caused by aging of the ovarian stroma, in which recruited follicles (and their eggs) mature after recruitment. The theory further argues that, in contrast to often genetic damage that over time affects eggs at resting stages, significant additional damage is encountered following recruitment during follicle maturation because of aging stroma that represents the microenvironment in which follicles mature. In contrast to the mostly genetic damages at resting stages, this “environmental” damage imposed by the ovarian microenvironment can, however, be remedied at least partially, by supplementing factors to the microenvironment that have gone lost with aging.

Treating the aging ovaries for better-quality eggs

The classical example CHR investigators have been quoting in supporting this point, is supplementation of ovaries with androgens (mostly dehydroepiandrosterone, DHEA) in women with low testosterone values, which has been proven highly effective (please note the conflict statement at the end of this article). Another example is the recently growing utilization of human growth hormone (HGH) in IVF practice. Like androgen supplementation, HGH supplementation (via IGF-1) acts on small growing follicles, which is the initial maturation stage of follicles after recruitment. Both supplementations, indeed, synergistically support the impact of FSH on follicle growth, resulting in more and better-quality eggs. To achieve this benefit, so-treated follicles in small growing stages must, however, be allowed to continue maturing for at least another 6-8 weeks before they reach the so-called gonadotropin-sensitive phase of folliculogenesis, when these follicles become responsive to fertility drugs. To supplement DHEA and/or HGH only during cycle stimulation, therefore, makes little sense.

Though so far no other components of the ovarian microenvironment have been identified that may benefit from supplementation at advanced female ages (or in younger women with premature ovarian aging or POA, also called occult primary ovarian insufficiency or oPOI), logic suggests that there must be a significant number of other biological factors that change in concentrations within ovaries over time and, therefore, if properly supplemented, might be helpful in improving follicle maturation.

CHR investigators also in recent years discovered (and reported in the medical literature) that biological processes within follicles, which are fully dependent on the surrounding stroma for nutritional support, accelerate. At CHR, this discovery led to routine utilization of Highly Individualized Egg Retrieval (HIER) in older women and younger patients with POA/oPOI, a treatment change which has radically advanced IVF practice over the last three years.

Advancing female age is, thus, such an important predictor of pregnancy and live birth chances in a quantitative as well as qualitative way, since egg and, therefore, embryo numbers and, in parallel egg and embryo quality, in IVF cycles decline. As science so far cannot, yet, produce “new” eggs, the only therapeutic interventions that can be pursued is making ovaries perform at what currently can be defined as their maximal potential. And that, as noted above, requires that older ovaries, whether “older” because of female age or POA/oPOI, be adequately “prepared” prior to every IVF cycle and that the ovarian stimulation during the IVF cycle be specifically adjusted to patients’ ages through the HIER process and to other specific requirements patients’ histories mandate. Such radical individualization of IVF cycle management is, therefore, currently the only tool that allows for improvements in IVF outcomes in complex IVF patients, whether younger or older.

Do women in their 40s need egg donation because of age?

Unfortunately, this message is only starting to resonate among IVF centers; most, indeed, still find it easier to simply advance complex patients into egg donation. These pages have repeatedly addressed CHR’s opinion that far too many, especially younger, women are ending up prematurely in donor egg cycles. We, therefore, here do not want to be repetitive, but this problem appears to be growing exponentially with the increased use of chromosomal testing of embryos prior to transfer (now called preimplantation genetic testing for aneuploidy, PGT-A), which results in the unnecessary discarding of large numbers of entirely normal embryos.

CHR’s physicians over the last two to three years have been struck by the increasing number of younger women, often in their 30s, who, at many IVF centers, after at times only one or two IVF cycles, were advised that “their only chance of pregnancy was egg donation” because none of their embryos was reported as “euploid” (i.e., chromosomally normal). It is, of course, one thing to issue a premature recommendation for donor egg use to a woman in her mid-40s. However, to make such a recommendation to a young woman who, likely, is still in a very fertile time period of her reproductive life is really inexcusable.

Conflict Statement
CHR and some of the center’s physicians are co-owners of a number of U.S. user patents that claim therapeutic benefits from androgen (including DHEA) supplementation in certain women with infertility. CHR and some CHR physicians also receive royalties from these patents from Fertility Nutraceuticals LLC, of which Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, is also a shareholder.

This is a part of the September 2018 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.