CHR Update

The following articles represent an update on CHR activities. If you want further information on any of these articles, please contact us. CHR is a comprehensive fertility center in New York, NY.

December 2011

It has become our tradition to summarize CHR's accomplishments over the preceding year in the December UPDATE. In this issue, too, we will follow the precedent, though with the understanding that simply too many good things have happened during 2011 to have all noted in this short space. We, therefore, suggest to readers of this UPDATE that they follow links for further details, where offered.

You may also want to visit fertility news releases CHR intermittently issues and selected fertility blogs, whether related to specific CHR matters or to topics in the news. We believe you will find them quite educational; they certainly shed light on what CHR stands for!

We also do not have the print space to list all of the center's 2011 peer reviewed publications, which either have already appeared or are in press. For this information, the reader is referred to CHR's fertility research publication list or the CVs of Drs. Gleicher and Barad.

Only so much: We again had a record year, both in quantity and quality. The latter is probably best demonstrated by expansion of CHR's publication range into highly prestigious medical journals with wider publication scopes than just reproductive endocrinology and infertility. Because of their wider publication scope, these journals accept fewer manuscripts in any given area, making it much more difficult to get a submission accepted.

Like in 2010, CHR's authors, once again, published a paper in PLoS ONE, considered the leading general medical electronic journal. CHR authors, for the first time, also have a paper in press in the very prestigious Journal of Clinical Endocrinology and Metabolism (JCEM), which, as official journal of the Endocrine Society, covers all of medical endocrinology.

Acceptance of CHR manuscripts in these and similar journals demonstrates the increasing recognition of CHR's research efforts beyond the medical infertility community of scientists!

DHEA Update (please note conflict of interest statement in the 2nd paragraph)

Our patent attorneys recently received notice that, likely before the end of 2011, CHR will be issued a second U.S. patent for utilization of DHEA, this time going beyond claims of improved pregnancy chances and fertility, validating that DHEA supplementation reduces aneuploidy (chromosomal abnormalities in embryos).

Therefore, we, again, reemphasize potential economic conflicts of interest in presenting DHEA data. Those potential conflicts should be carefully considered in interpreting here presented DHEA data.

The importance of this second patent cannot be overemphasized: not only does it reemphasize the seriousness of CHR's DHEA research but also, for the first time, presents an at least partial explanation why DHEA is clinically so effective.

In his excellent opening keynote lecture at this year's ESHRE Meeting in Stockholm, Sweden, Terry Hassold, PhD (Washington State University), emphasized, as quoted by the September 2011 issue of Focus on Reproduction, the monthly magazine published by ESHRE, "the magnitude of the challenge of aneuploidy in the human," and how "staggered" he was by the frequency of abnormalities that are seen.

Chromosomal abnormalities in humans are, indeed, staggering, and not only as causes of increasing infertility with advancing female age but also as the most common causes of increasing miscarriages. This second DHEA patent is, therefore, potentially of even greater importance than the earlier recognition in the first patent that DHEA increases fertility in women with diminished ovarian reserve (DOR), since it hints at possible causes of chromosomal abnormalities, and suggests that, at least to a degree, they can be prevented by pharmacological interventions.

Reducing chromosomal abnormalities has been a "holy grail" of IVF for many years. The whole concept of preimplantation genetic screening (PGS) is based on the idea of only transferring euploid (chromosomally normal) embryos into the uterus. This, then, is expected to improve IVF pregnancy rates and reduce miscarriage rates. DHEA may, at least partially, achieve both goals in a much less invasive and more cost-effective way.

Reduction in aneuploidy with DHEA, by definition, reduces miscarriages. We previously reported that miscarriage rates in DHEA-supplemented women with DOR were, depending on statistical analysis used, between ca. 50% to 80% below expected miscarriage rates in a general IVF population. Not surprisingly, this effect becomes apparent after age 35 and increases with advancing female age [Gleicher et al. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. Reprod Biol Endocrinol. 2009;7:108.].

An argument can, therefore, be made that DHEA supplementation may improve pregnancy chances and decrease miscarriage rates for all women above age 35 years. Maybe, in women above age 35, DHEA should become a part of a prenatal supplementation schedule that already includes folic acid and vitamins.

A new concept of ovarian aging

Regular readers of the UPDATE will recall that, over a year ago, based on our DHEA work, we reached the conclusion that the understanding of ovarian aging, likely, requires reevaluation. It is generally believed that women are born with all of their eggs. These eggs sit on the periphery of the ovary in a very immature form within structures called the primordial follicles (PFs) and wait to be recruited into what is called folliculogenesis (or follicle maturation), a process that spans many months.

Once a female enters menarche, and starts menstruating, she constantly recruits large cohorts of follicles into this maturation process, over time depleting the pool of eggs she was born with. How many PFs a woman has left, therefore, defines her ovarian reserve (OR) or ovarian age.

Medical dogma has held that, as women age, not only do they lose OR but the quality of their eggs "in storage" deteriorates in parallel. And it is the damage from this egg aging process that leads to more aneuploidy and, therefore, to higher miscarriage rates.

In observing outcomes in our DHEA-supplemented patients, we were quite stunned by low miscarriage rates, as discussed above. Low miscarriage rates are indicative of good oocyte (egg) health. It, therefore, appeared unlikely to us that already age-damaged eggs could, after DHEA supplementation, still give us such outcomes. In searching for an explanation for the observed low miscarriage rates, we, therefore, concluded that our understanding of ovarian aging, likely, required revisions.

We developed a hypothesis that eggs a woman is born with are stored in their PFs, like "in a freezer," at very low metabolic rates. At that stage, they do not age significantly. What does age, in contrast, is the ovarian environment into which these PFs are recruited for their months-long maturation. This environment matters, and an egg recruited in an older woman will undergo maturation in a much worse ovarian environment than an egg recruited at a younger age.

It, therefore, is the ovarian environment that ages, and not the egg itself! Why is that important? Because it appears very unlikely that an age-damaged egg can still be resuscitated. In contrast, it almost appears obvious that an aged ovarian environment can be improved if properly supplemented to recreate the conditions of younger age.

This is what DHEA apparently does (DHEA significantly declines with advancing female age). What, very likely, should drive further advances in treating older women's infertility is that we, hopefully, will discover additional agents with similar ability to improve ovarian environments.

The Ovarian Club

In November, CHR's Medical Director, Dr. Gleicher, was given the honor of speaking at the 1st Ovarian Club Meeting in Barcelona, Spain. This is a new forum meant to bring together the most interesting investigators of the ovary from all over the world in hopes of achieving "cross pollination." The goal was probably exceeded by a wide margin, because all active participants (as well as a large audience of clinicians) were exuberant in their responses to the meeting, which, undoubtedly, will become an annual event now.

Presentations of CHR's DHEA data, and above noted hypothesis about aging of the ovarian environment rather than of eggs (which was extremely well received), were given unwitting corroborative evidence by two other colleagues: Dror Meirow, MD, from Israel, presented very interesting data on the histological effects of chemotherapy on ovaries in young cancer victims. He demonstrated significant damage to already recruited follicles, with PFs remaining basically untouched, thereby confirming the concept of PFs actually representing oocytes "in the freezer" at very low metabolic rates, and, therefore, resistant to damage until recruitment.

In a spellbinding presentation, John Eppig, PhD, from Jackson Laboratories in the U.S., reported on his laboratory's quite advanced efforts of building an in vitro follicle maturation model. In his concluding sentence, he noted, "with some embarrassment," that "granulosa cell function in his model improved the most with DHEA-supplementation," again emphasizing the importance of the ovarian environment (and, of course, of DHEA).

In his second presentation, Dr. Gleicher reported on CHR's FMR1 research. This lecture was equally well received, and, it appears, may lead to collaborative research efforts with colleagues from The Netherlands and, possibly, Israel.

A commercial DHEA product (Please consider above noted conflict statement carefully)

CHR is widely recognized as the infertility center that introduced DHEA to infertility treatment. In the six years since the first of many CHR publication on DHEA appeared, DHEA has found application all over the world. Ever since, we have been receiving daily queries from colleagues and members of the lay public, asking which DHEA we prescribe, whether we have any preferences in regards to the many products available on the web, whether we prefer plant or animal derived DHEA, whether micronization is really important, what dosages we recommend, etc.

In the USA, where it is considered a food supplement, DHEA is available over the counter without prescription. In most other countries, where DHEA is available, it requires a prescription. In a few countries, DHEA is even considered a controlled substance or not available at all.

We always prescribed the same DHEA to our patients. Our published studies, therefore, were largely based on one kind of DHEA for which we wrote prescriptions, which our patients filled at compounding pharmacies. During all of these years, we never derived any financial benefit from prescribing DHEA. Indeed, we refused a number of offers to endorse and/or start utilizing particular brands, because we wanted to be certain our patients continued to receive exactly the same DHEA product with which we had initiated our studies.

Practically all major pharmaceutical companies with products in our area of medicine rebutted during those years our attempts to get them interested in DHEA. None considered the potential market for DHEA large enough to warrant their interest and investment.

We are delighted to announce, however, that this year, finally, a company was formed to produce a DHEA product that fulfills all of our requirements, and warrants our endorsement. In early 2012, such a product will reach the market. It will offer a plant-derived DHEA, expertly manufactured, guaranteeing consistency. The DHEA will be micronized to the same particle sizes as the compounded DHEA we used in all published CHR studies. Independent batch controls in an outside laboratory will make sure of that.

The product will be available in pill form to avoid capsule materials, which may present issues for patients keeping kosher or halal. Moreover, the pills will be packed in individual blisters, 3 x 7 per sheet (the exact supply for a week, according to the CHR prescribing protocol), with 4 sheets making up a box of one-month supply.

The DHEA product will be produced by FERTILITY NUTRACEUTICALS, LLC, under the brand name FERTINATAL™, and will be the first DHEA product endorsed by CHR. It will also be significantly less costly than the compounded DHEA that we have prescribed until now.

As always has been the practice at CHR, where there are choices between different medications, supplements or vitamins, we leave the choice to our patients. Our principal interest has always been that patients receive the best possible medications they need at the lowest possible cost. Even though we do endorse FERTINATAL™ as what we now consider, overall, the best DHEA product on the market, our patients have absolutely no obligation to use FERTINATAL™. Once it becomes available for purchase at CHR in early 2012, just as before, every patient will still have free choice to continue using compounded or other over the counter products.

Full disclosure, in attempts to avoid even the slightest suspicion of conflicts of interest, has always been a cardinal rule at CHR. It, therefore, is of utmost importance to us that every patient understands the financial relationship between CHR and FERTILITY NEUTRACEUTICAL, LLC, which will allow CHR to make a modest profit from the sale of FERTINATAL™.

Oocyte (egg) freezing

With the recent introduction of our Eco-Donor Egg Program (EcoDEP), we significantly expanded our egg freezing effort. CHR, of course, has been freezing eggs for many years, but the principal reason for egg freezing, up to the establishment of the EcoDEP, was fertility preservation, whether in young women after cancer diagnosis, and in need of chemo- or radiotherapy, or in women electively seeking the procedure to prolong the time for reproductive options.

With the advent of oocyte vitrification as preferred modality for egg freezing, results have improved enough for us (and others) to start considering oocyte (egg) banking (akin to sperm banking, which has been routine for decades).

Oocyte vitrification has been a major topic of ESHRE and ASRM meetings this year. It appears that this method of egg freezing has clearly won out over the older method of slow-freezing. CHR's embryologists, under the leadership of Ping Xia, PhD, MD, are very well versed in vitrification methods, and our staff is looking forward to demonstrating their expertise with the new EcoDEP.

Despite rapid progress, and greatly improving results with egg freezing, CHR, for the time being, and in agreement with authoritative recommendations from ASRM/SART and ESHRE, continues to classify egg freezing as an experimental procedure. Any form of egg freezing will, therefore, require the signing of an "experimental" consent.

CHR's egg donation program vs. programs outside the U.S.

CHR now offers two distinct programs for use of donor eggs: Both programs are well described on our website, and we refer all interested readers to the site. What warrants further emphasis, however, is a comparison of CHR's Standard Donor Egg Program (SDEP) with similar standard programs, utilizing fresh egg donor cycles, especially in Canada and Europe.

After the recent opportunity we had to discuss egg donation with colleagues from outside the U.S., principal differences immediately come into focus: The principle difference between CHR and those other programs is, clearly, choice! Both in Canada and in Europe, recipients really have little, if any, choice in donor selection. In Canada, the prohibition of paying egg donors for their services has created long waiting lists, and, of course, as a consequence, little choice for recipients. The situation in the United Kingdom is very similar.

In the rest of Europe, the situation is even more complicated: In most countries, egg donation is prohibited. Consequently, patients cross borders from those non-permissive countries into a few permissive countries, mostly Spain and the Czech Republic but also Russia, Romania and (Turkish) Cyprus. Programs in all of these latter countries have an abundance of egg donors (who are usually reimbursed very poorly for their efforts), are permitted to offer egg donation, but still often face important legal restrictions. In addition, they usually have homogeneous populations, meaning that their multi-ethnic choices are limited.

More importantly, however, the donor information made available to recipients is minimal at best. In Spain, where most of Europe's egg donations are performed, it is, indeed, forbidden by law to offer any significant information about the donor except for in medical emergencies, and it is not allowed to show donor photographs.

Contrast all of this to CHR's egg donation program, where donors of practically all ethnic backgrounds are available for immediate "matching." And the emphasis here is on the word "matching," because we can really match donors to their recipients and/or the recipient's desired donor characteristics. We also have what we call "a book" about each donor, and, therefore, can really offer very detailed descriptions of not only the donor's main characteristics but even of her likes and dislikes, hobbies, etc. Finally, almost all of our donors allow us to show their photographs, and many now also make short videos for us. Our recipients, therefore, always have multiple choices in selecting their donors!

And, before we forget, last U.S. and European ESHRE data still suggests significantly higher pregnancy rates in egg donation cycles in the U.S. Putting all of this together, maybe there are good reasons why costs for egg donation in the U.S. are a little higher! It actually is quite surprising how small the cost difference has become, given the strength of the Euro.

Concluding for the year

While we could go on an on, there is only so much space we are allowed for these pages (and we exceeded the allotted page volume already).

2011 was an excellent year for CHR, and, as outcome statistics demonstrate, at least an equally good year for CHR's patients. And this is what it really is all about, with only one purpose in mind: to improve clinical outcomes for our patients.

Considering that approximately 90 percent of new CHR patients have previously failed treatments elsewhere, CHR's outcome statistics are nothing but remarkable. When one deals with patients with the most difficult cases, every percentage point of pregnancy rates counts, and improvements in outcomes are, therefore, painfully slow. To attend major scientific meetings, and to read in the medical literature that colleagues don't even attempt treatment in women, who would, at CHR, still rather routinely conceive, is, therefore, most rewarding.

We wish you and your loved ones a Very Happy Holiday Season and a Healthy, Happy and Prosperous New Year, and are looking forward to an even more successful 2012 for our patients and all of CHR.

Contact Us

If you have any questions or comments, please contact us.

-The CHR

Last Updated: December 23, 2011