CHR Update December 2005

The Aging Ovary

The female ovary, unfortunately, ages. In approximately 90% of women this aging process takes place along a well defined aging curve and ends when full menopause is reached (age 51 is the average age of menopause). However, in approximately 10 % of women, this aging process occurs prematurely and therefore, such women experience early menopause. Thus, we now differentiate between physiologic and premature ovarian aging.

Dr. Norbert Gleicher explains what early and premature menopause is, how it is linked to diminished ovarian reserve and the use of DHEA supplementation for improving ovarian reserve.

A number of investigators, us included, have in recent years suggested that these two aging processes may be identical and that premature aging simply represents a shift of the traditional aging curve towards earlier age. This opinion was mostly based on observations which showed that women with early ovarian aging developed many of the same ovarian function characteristics as older women, – just at a younger age. These characteristics included: (1) evidence of decreasing ovarian reserve (i.e. abnormal ovarian function testing); (2) poorer egg and embryo quality; and (3), of course, lower pregnancy rates.

However, some very recent studies have led us to question the universality of this premise. While we still believe in the principle of premature ovarian aging (POA), we no longer believe that it is reflective of all the typical characteristics of the physiologically aging ovary. Indeed, we have considerable reason to believe that the young woman with POA lacks one of the most classic features of the physiologically aging ovary: greatly increased number of chromosomally abnormal (i.e. aneuploid) eggs. And this is really good news!

The first hint that there may be a difference between these two groups of patients came from a number of studies which all agreed that abnormal ovarian function tests (especially the so-called baseline FSH level) were of less negative predictive value when found in younger women. Our suspicion then grew further when, to our pleasant surprise, we noted in a retrospective case controlled study, that, with an adjusted ovarian stimulation protocol, we were able to achieve a 32% ongoing clinical pregnancy rate in young women (under age 35) with POA. This was a much higher pregnancy rate than expected for such a population and suggests that, while POA patients produce fewer eggs, the ones they do produce, are still of surprisingly excellent quality.

Egg quality declines with advancing female age, and the principle reason for this decline is believed to be a steady increase in chromosomal abnormalities. We, and others, expected that the same increase in chromosomal defects would also be observed in women with POA. Above noted observations in women with POA questioned this premise, however.

Andrea Weghofer, M.D., Ph.D., originally from Vienna, Austria, is currently a research fellow at Yale University School of Medicine and works with us, at CHR, one to two days a week. She decided to tackle this question in a research project, in which she retroactively looked at matched pairs of women with either POA, or normal ovarian function, who had undergone preimplantation genetic diagnosis (PGD) for aneuploidy testing at our Center. Based on our earlier observations, by this point, we were no longer surprised about her findings:
Women with POA did, indeed, not show an increase in chromosomal abnormalities as women with physiologically aging ovaries do.

We cannot go into any more detail about this study at this point because we are planning to publish those details in a scientific journal. However, as already noted earlier, this is, once again, excellent news!

And here is why: First, these chromosomal data confirm above mentioned reports that such evidence of POA, as elevated FSH levels, in younger women have much less adverse prognostic significance than in older women. This is an issue of crucial importance because at many IVF centers, women with elevated FSH levels, even if young, are either refused entry into IVF cycles or are cancelled before retrieval, if they do not produce adequate follicle numbers. They are, thus, never given the chance of conception with their own oocytes, even though they produce oocytes of excellent quality. Even small numbers of oocytes will, therefore, still give them an excellent pregnancy chance. Such patients should, therefore, not be sent prematurely into egg donation.

In addition, however, these findings also suggest that it is really worthwhile to try to increase egg and embryo numbers in women with POA (through the use of DHEA) because, by doing so, we don’t only increase genetically abnormal
egg numbers. And this second conclusion, of course, brings us to the major area of research at CHR over the last 18 months: The DHEA Story.

The DHEA Story

We have offered during 2005 a number of “Updates” in regards to our ongoing DHEA research and don’t want to be repetitive. Only so much in the format of a summary: our data so far suggest that DHEA
in women with aging ovaries

  • Increases egg and embryo numbers
  • Improves egg and embryo quality
  • Increases spontaneous and IVF pregnancy chances(i.e. cumulative pregnancy
  • Reaches peak effectiveness after at least 4 months of use
  • Maybe, also reduces chromosomal abnormality (aneuploidy) rates in eggs and

These effects of DHEA are seen in women with physiologically aging ovaries (i.e. in older women) as well as in women with POA. Indeed, a recent life table analysis on our data revealed that the highest cumulative pregnancy rates are seen in younger women with POA, though the DHEA effect is seen at almost identical degree in women up to age 42 years. Above that age, the DHEA effect diminishes but still remains significant.

Since we now know that women with POA do not demonstrated an increased prevalence of chromosomal abnormalities, as was feared in the past, DHEA usage in such patients appears particularly worthwhile. This is, of course, confirmed by the superior pregnancy rates we have witnessed in such patients. (A manuscript, detailing all of these data, has just been submitted for publication to a scientific journal.)

Whether DHEA treatment, indeed, reduces chromosomal abnormalities may be the single most important question and, unfortunately, remains the only question we, so far, have not been able to answer with certainty. We, therefore, just
submitted a new research proposal to our Institutional Review Board (IRB) for approval (which was granted) in which we requested permission to treat young egg donors, alternatively with DHEA and placebo, and determine the aneuploidy
rate in their embryos.

If you are a patients, currently considering an egg donation cycle as an embryo recipient, and if you are interested in participating in this study, please contact us.
Our Center has probably more (over 150 pre-screened) oocyte donors (of practically all ethnicities) available for immediate match than probably any other IVF center in the nation.

Moreover, if you don’t have a medical indication for PGD, our Center will give you the potential benefit of PGD, free of charge.

Is Premature Ovarian Aging (POA) an Adrenal Disease?

We reported in a previous “Update” the likely association between POA and an incomplete (or partial) adrenal enzyme defect, called 17,20 desmolase deficiency.
(A manuscript on this unusual case has been submitted for publication.) When we announced this observed association, which leads to low DHEA levels, and is, therefore, compatible with our hypothesis that DHEA substitution, in many
cases, may improve ovarian function, we also announced that we would continue to look for adrenal enzyme defects in young women with POA.

This study is now in progress and we have so far investigated approximely 10 women. To our surprise, we have found an unexpectedly high prevalence of abnormal ACTH stimulation tests in these women and these findings,
therefore, are raising the question whether POA, at least in many cases, may not represent an adrenal disease.

Ten cases are, of course, not enough to reach any serious conclusions. We are, therefore continuing to accumulate cases and are also looking forward to cooperating with other investigators who have the technical ability to test for adrenal enzyme defects by genomic means. Such an approach towards the diagnosis of adrenal enzyme defects is currently still largely limited to research labs and has not been widely used clinically. However, if we want to be sure about our diagnoses, we feel that this is the way we need to proceed.

For this study we are seeking young women (preferably under the age of 35) who were diagnosed with abnormally elevated FSH levels. If you are such a woman, and are interested in participating in a clinical evaluation that may shed new light on your condition, please contact us by calling 212-994 4400 or click here.

We would like to conclude this last “CHR UPDATE” of the year by wishing you all a peaceful Holiday Season and a Healthy and Prosperous New Year 2006…

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.