CHR Update

The following articles represents an Update on CHR activities. If you want further information on any of these articles, please email Tom Weidner.

February 2008


With February 1, as the deadline for submissions to the Annual ESHRE (European Society) Meeting which, this year in June, will take place in Barcelona, Spain, CHR investigators had an extremely busy January preparing materials. The result was a record breaking eight submissions, many including extremely exciting new results with considerable potential clinical importance. Here are a few selected summaries:

EXCITING NEW DHEA NEWS

We, encourage interested parties in learning more about prematurely aging ovaries to contact us.

We have known for quite some time that many centers around the world have routinely started using DHEA. One of these centers has been Toronto West Fertility Associates, in Toronto, Canada. We have intermittently heard from them that anecdotally they had similar results to ours, but last December they were kind enough to send us their whole, meticulously kept data bank on DHEA usage at their center.

Their pregnancy experience results were, indeed, very similar to ours. What we, however, were most interested in this time was not pregnancy, but miscarriage rates. As we have repeatedly noted in our UPDATEs, we have come to believe that DHEA supplementation may reduce the number of chromosomally abnormal embryos (aneuploidy). We reached this conclusion after making two observations:

(1) In a small number of women who underwent PGD after they had been treated with DHEA, we found lower aneuploidy rates than in women without DHEA supplementation. Unfortunately, women in need of DHEA usually have small embryo numbers and, therefore, only very rarely qualify for PGD. This kind of data accumulation is, therefore, very slow and we so far have not reached statistically robust enough numbers.

(2) Our second, related observation was that we noted a surprisingly low miscarriage rate in DHEA pregnancies. Since miscarriages, especially in older women, are mostly due to chromosomal abnormalities, this observation, too, suggested the possibility that DHEA may reduce aneuploidy rates. To reach statistically robust conclusions, once again relatively large (pregnancy) numbers were required and we therefore, up to this point, have been cautious to not over interpret our own data.

This is why the timing of the arrival of the Toronto data was so exciting; these data not only confirmed the high pregnancy rate in very unfavorable patients with diminished ovarian reserve, but demonstrated an identical reduction in miscarriage rate to the one observed by us (when compared to national IVF data). Since the combined data sets between CHR and the Toronto center involve an adequate size patient sample, we are now confident to state that DHEA supplementation significantly decreases the miscarriage rate in women with diminished ovarian reserve.

Indeed, we even can go beyond this statement: While a reduction in miscarriage rates is seen in women of all ages, the reduction is smaller in women below age 35 than in women above age 35 years, where the reduction often exceeds 50 percent. This, of course, should not surprise since miscarriages are known to increase with advancing female age. Most of these miscarriages are, however, due to aneuploidy and this observation brings us back to where we started from: Our new data, on the decrease in miscarriage rates after DHEA supplementation especially in older women above age 35, strongly support that DHEA, indeed, reduces chromosomal abnormalities (aneuploidy rates) in embryos.

The importance of this observation cannot be overemphasized. Since older women represent in the USA the most rapidly growing age group of women having babies, our findings may have significance far beyond those older women who require fertility treatment. Indeed, if confirmed by further studies, DHEA may become a supplement to be given, like prenatal vitamins, to all (older) women contemplating pregnancy.

We, of course, have submitted an abstract on this exciting data to ESHRE and a full length manuscript is in preparation.

As a final news item in regards to DHEA, we are getting ready to launch the prospectively randomized DHEA study in younger women (under age 38) with so-called unexplained infertility, which we previously announced for early 2008. If you are interested in participating and/or are a physician who wants to have one of your patients considered for this (free of charge) study, please contact us.

FMR1 (FRAGILE X) GENE DEVELOPMENTS

You will recall that we, not too long ago, reported the discovery that, based on the number of triple CGG expansions on the FMR1 gene, premature ovarian aging (POA) could be predicted. We also noted that we had defined two principal causes for premature ovarian senescence, a genetic one, defined by excessive triple CGG expansions on the FMR1 gene, and an autoimmune form, which occurred in young women who demonstrate autoimmune abnormalities in their blood. Even though both forms could, on rare occasions, occur in the same woman, most, patients with POA suffered from one or the other form.

We also noted that we had submitted the preliminary data, involving only 40 patients, for publication. We are now very pleased to report that two manuscripts, describing this data, have been accepted by the prestigious medical journal Fertility and Sterility and are now in press. The manuscripts should appear electronically within a few weeks and later on in print in the paper version of the journal.

We have since, however, expanded our investigation of the association between triple CGG repeats and ovarian function to 158 patients and this much larger and, therefore, much more robust database, confirmed our earlier findings to a large extent. We submitted two abstracts of this work to ESHRE and a full length manuscript has already been submitted for publication.

Our new data strengthen the previously reported association between abnormally high triple CGG repeat numbers and risk for POA. We are now even more convinced that FMR1 testing should become an integral part of any infertility evaluation, and that women with 35, or more, triple CGG repeats are at increased risk for POA. In addition, any autoimmune abnormality also predisposes to POA.

We, encourage interested parties in prematurely aging ovaries to contact us.

IS FSH TESTING OUTDATED?

Everybody following the research efforts at CHR by now knows that we for a long time have been very concerned with accurate ovarian function assessment. It is for that reason that we introduced to the literature the concept of age-specific ovarian function testing (Barad et al. Obstet Gynecol 2007;109:1404-10), which we have proven to be much more accurate than regular ovarian function testing.

The traditional ovarian function test has been follicle stimulating hormone (FSH). More recently however, another test- the so-called anti-mullerian Hormone (AMH)- has been increasingly utilized in the literature. We now have reached the conclusion that AMH testing reflects ovarian reserve better than FSH. Our conclusion is based on two observations: (1) When correlating triple CGG repeats on the FMR1 gene with ovarian reserve, we found, at least in the clinically most important expansion range between 35-55 repeats, a strong statistical correlation with AMH, but not with FSH. (2) In a study, recently submitted to ESHRE, we found that AMH correlates much better than FSH to the number of oocytes retrieved in IVF.

This, of course, does not mean that FSH testing should be abandoned, especially if it is done in age-specific ways, but it suggests that we may be in the midst of a paradigm shift, from predominance of FSH testing, to priority for AMH evaluations. AMH has, of course, the additional advantage of being stable throughout the cycle. In contrast to FSH, which should be drawn on cycle days 2/3 only, it can, therefore, be obtained at any time. AMH has the additional advantage of not being influenced by other hormones. A high estradiol level can, for example, artificially reduce FSH levels and give the false impression of a normal FSH.

We consider AMH values above 1.5 ng/ml as normal. Levels below 1.0 ng/ml are clearly abnormal and suggest diminished ovarian reserve. Our investigations suggest that a value of approximately 1.2 ng/ml corresponds to an approximate FSH value of 10.0 mIU/ml.

THE INSTITUTE FOR FERTILITY PRESERVATION

As we announced in the January UPDATE, CHR now has a new division, the Institute for Fertility Preservation (IFP). Even though Dr. Kutluk Oktay, its Medical Director, has barely started his activities here at CHR (and as Professor and Director of the Division for Reproductive Endocrinology and Infertility at New York Medical College), there are already a number of exciting new developments to report. For example IFP will, through Dr. Oktay, have a unique affiliate relationship with Memorial Sloan-Kettering Hospital, the premier academic cancer center in NYC, if not the nation. As part of this agreement, the hospital will hire a full-time physician assistant to exclusively coordinate fertility preservation efforts at IFP for their young cancer patients.

At the invitation of the Director of the NICHD of the National Institutes of Health (NIH), Dr. Oktay will also represent CHR and IFP at NIH Fragile X Research Coordination Group (FXRCG). In pursuing FMR1- related research over the last year, we were unaware that, at the urging of Congress, NIH had made research in regards to the FMR1 gene a fiscal priority for Fiscal Year 2008. Dr. Oktay will now join the ovarian insufficiency group (one of three working groups) of FXRCG.

We, encourage interested parties in fertility preservation to contact us.

MORE ON THE PGS FRONT

You will still remember our recent opinion on preimplantation genetic screening (PGS), voiced very clearly and loudly in the UPDATE and THE CHR VOICE, our quarterly newsletter. PGS, of course, is the use of preimplantation genetic diagnosis (PGD) for the purpose of improving IVF pregnancy rates and reducing pregnancy loss. We made the point that, in our opinion, PGS was being oversold by the IVF community and, if performed in poorly selected patients, the procedure may even reduce pregnancy chances.

We don’t want to be repetitive in our arguments. It is, however, satisfying to see that since we published our opinion, ASRM/SART also finally have found their voices and issued a new Practice Committee opinion (Fertil Steril 2007; 88:1497-1504), which concludes that available evidence does not support the use of PGS as currently performed to improve live-birth rates in patients with advanced maternal age, with previous implantation failure, in women with recurrent pregnancy loss and in women with recurrent pregnancy loss-related aneuploidy. In short, there is no proven indication for PGS, reaffirming the point previously made by us that PGS should be considered an experimental procedure and be performed as such only with appropriately worded informed consents. Suffice it to say, CHR has been utilizing such a consent for close to two years.

We actually believe that PGS may improve IVF outcomes and possibly reduce miscarriage rates, but only in a few very carefully selected patients. Who those are, awaits further scientific evaluation. As we, in a soon-to-be-published article suggest (for more details, see below), older women, currently widely considered the most suited candidates for PGS, may, indeed, be the worst, with PGS actually reducing their pregnancy chances. The best and maybe only suited candidates could be young women or older women with an unusually large number of oocytes and embryos.

Maybe as a further reflection of changing opinions in regards to PGS utilization, a manuscript, critical of current PGS practice patterns, based on a careful review of published literature by CHR investigators, was, after an almost two-year journey, finally accepted for publication (Gleicher et al. Fertil Steril; In press) and should soon be appearing in electronic form, later to be followed in print. One, of course wonders why such a paper was not accepted earlier. Many unnecessary PGS cycles, possibly, would never have taken place.

NEW CHAT ROOM FOR IVF PATIENTS

We thought that you might want to know that there is a new website/chat room out there in cyberspace, exclusively dedicated to IVF, called ivfLINK.com. Since we have been advised that the content of information materials will be carefully vetted, we suggest that you consider active participation in one or more of the IVF-related topics the site addresses. If the founders’ concept develops as expected, this website should, in the near future, become an interactive centerpiece for the Web-based IVF community. Click here to visit the IVF Forum website ivfLINK.

We hope you enjoyed our monthly UPDATE, which this time turned out a little bit lengthier than usual. But this is what happens when there is, simply, too much news to report from CHR. Dr. Gleicher’s (CHR Founder and Medical Director) motto has always been “never a dull moment” and nothing reflects better the current atmosphere at CHR - especially in these scientifically exciting days- where on a daily basis we feel that research at CHR is improving and advancing infertility care.

The CHR

PREVIOUS UPDATES

We will continue posting periodic UPDATES, when there are news to report from CHR. So, continue looking for them! These are exciting times at CHR, and we thank you for your interest in our work.

Last Updated: October 24, 2013