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CHR Voice - Spring 2009
Clinical Care·Research·Education
A newsletter provided by the Center for Human Reproduction
In This Issue...
- AMH and FMR1 Fertility Tests
- 2009: A Year of Controversies in ART?
- DHEA Baby Down Under: Patient Testimonial
- CHR in the Media
- Contact Us
CHR Offers Updated Fertility Tests for the Ob/Gyn Community

As we have reported in the past issues of VOICE, researchers at the CHR have been busy investigating two groundbreaking fertility tests in the past few years. One is the use of AMH (anti-Müllerian hormone) in place of the conventional FSH (follicle stimulating hormone), and the other is the CGG repeat counts on the FMR1 (Fragile X) gene. We have posted a concise reference on our website, but here are the details.

Our finding that AMH is a more precise indicator of ovarian reserve than FSH is closely linked to our ongoing investigation of DHEA. Over the last 18 months, investigators at CHR have become increasingly impressed by improved specificity of ovarian reserve testing with the use of AMH in place of standard FSH. They, indeed, recently published a paper (Barad et al. Fertil Steril. 2009 Apr;91(4 Suppl):1553-5.) and have another paper in press (Singer et al., Fertil Steril) on the subject. In parallel, colleagues worldwide have started reporting similar findings in regards to the better specificity of AMH in comparison to FSH in determining ovarian reserve.

This gave us the idea to investigate whether AMH may allow assessing changes in ovarian reserve following DHEA supplementation. We are now pleased to report that a recently completed study, indeed, for the first time, demonstrated improvements in ovarian reserve in association with DHEA supplementation. DHEA improves ovarian reserve, both in younger women with premature ovarian aging (POA) and in older women with physiologic diminished ovarian reserve (DOR). However, not surprisingly, DHEA’s positive impact on ovarian reserve is more pronounced in younger women.

As a fertility test, AMH has several advantages over FSH. AMH is now considered a more accurate reflection of ovarian reserve than FSH, and AMH levels can be drawn independent of a woman’s cycle date. Seeing the clinical potential of AMH in diagnosing POA, we have developed age-specific cut-off values for AMH (see Table 1), just as we did for FSH a few years ago, for the use by Ob/Gyn physicians.

The values were calculated based on 95% CI of age bins, using CHR’s patient population. Please note that CHR’s patient population is, even for a fertility center, extremely adversely selected and contains a very high percentage of women with severely diminished ovarian reserve. These cut off values are, therefore, likely conservative. Average practitioners should, therefore, start considering a diagnosis of POA even with slightly lower age-specific FSH and slightly higher age-specific AMH levels than reported in the table.

We at CHR hope that these age-specific cut-off values will increase the chance that women with POA receive accurate diagnosis in a more timely manner, as even in competent fertility centers, POA is very frequently overlooked (Barad et al., Obstet Gynecol 2007; 109: 1404-10.), thus delaying treatment for patients with the “ticking time bomb” of rapidly diminishing ovarian reserve.

On the FMR1 gene front, we were able to demonstrate that the number of CGG repeats on this gene is statistically correlated to the risk towards POA (i.e. early DOR). Among various studies that we have under consideration in various journals, we learned what represents a normal range of CGG repeats on the gene in regards to ovarian reserve, and we were able to demonstrate that this normal range is identical in all races (see Table 2). Even more importantly, we have been able to demonstrate specific ovarian aging curves, dependent on whether both alleles of a woman were in this normal range or one (heterozygous) or both (homozygous) of her alleles showed abnormal counts. Indeed, in one paper, which is now in press, we demonstrate that the CGG count on the FMR1 gene, like AMH, is predictive of oocyte numbers (Gleicher et al., Reprod Sci 2009; 16:462-7.).

CHR’s investigators are now intrigued by the observation that, depending on whether CGG counts are normal, heterozygous or homozygous, ovarian aging appears to happen at different speeds. This may have very significant implications for infertility treatments, especially at more advanced female ages, because CGG counts may turn out to be predictive of responses to such treatments.

It is at this time still a little premature to go beyond this point, but for now, we are confident to say that women with either fewer than 26 or more than 32 CGG repeats are at increased risk for prematurely diminished ovarian reserve. The evaluation of CGG counts on the FMR1 gene, thus, allows for prospective risk assessment of young women as to their risk towards POA. Since the number of CGG repeats on the FRM1 gene is fixed from birth, a determination that a woman has over 32 or under 26 repeats should lead to careful, prospective ovarian reserve monitoring.

As our investigation continues, we are optimistic that CGG counts on the FMR1 gene will allow us to better stratify patients for specific treatment choices. For example, we would not at all be surprised if CGG counts allowed us to predict which women may better respond to DHEA supplementation or which women above age 45 years may still be able to produce eggs and embryos.

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2009: A Year of Controversies in Assisted Reproduction?

So far, 2009 seems to be the year of controversies in the field of Assisted Reproductive Technologies (ART). To start, there were the octupulets born through IVF in California. Then, an IVF clinic claimed that they are capable of creating embryos with physical traits of parents’ choice, reigniting the old fear of “designer babies” from the early days of IVF. As if that wasn’t enough, a group of researchers then came out with a paper suggesting that the rate of birth defects increases after IVF. For each of these developments, CHR’s Medical Director, Norbert Gleicher, MD, made CHR’s position clear, in his effort to fight misconceptions created by the irresponsible minority in the specialty.

Implications of the Octupulet Case

As we don’t wish to add too much to the farce surrounding the Californian octupulets, we will limit our commentary here to the legal implications of the case. The case sparked calls for more regulatory intervention from a wide range of commentators, including the otherwise conservative Bill O’Reilly. The media, however, failed to note that probably no medical field was as strongly ‘regulated’ by state and federal rules as IVF. They also failed to note how rare such obvious transgressions of voluntary guidelines were.

Some media organizations, therefore, only too willingly jumped on a recent announcement by the CDC, which claimed that a large majority of IVF programs transferred more embryos than recommended by the ASRM/SART guidelines. What CDC (and the media) did not note in their announcement is that ASRM/SART guidelines, correctly in our opinion, allow for some flexibility in the number of embryos transferred. While basic numbers of recommended transferred embryos are determined by age of the woman, guidelines allow at every age for a small range, based on secondary factors, such as ovarian functional reserve (i.e. number of eggs retrieved), embryo quantity and quality, and prior IVF cycle experiences. As meant by the guidelines, those secondary factors will always result in upward adjustments in suggested embryo numbers, to compensate for unfavorable factors, but will be invisible to CDC statisticians.

When asked, on a MSNBC News program, about potential legislative control over the number of embryos to be transferred, Dr. Gleicher, rather categorically opposed more stringent regulation of the number of embryos transferred. He equated such an approach to recommending that “legislative control over newspapers be mandated after one journalist is caught making up fictitious stories.” He then in the same program picked up on a suggestion made by CHR’s business manager Jolanta Tapper (always the business person) during in-house discussions about the octuplets, when she, half serious and half joking, suggested that, “maybe, the physician in this case is best held responsible for the octuplets’ education costs.”

Designer Babies?

After the news cycle about the California Octuplets finally appeared to have run out of steam, there came yet another California-based colleague of ours, who found it necessary to stir up the public with the announcement that, starting in 2010, his clinic will offer patients the ability to select embryos for cosmetic traits, such as eye color, hair color and even skin tone.

The media, of course, had another field day because, primed by an obviously inappropriate medical provider in the octuplets case, here, quite apparently, was once more convincing evidence for the irresponsibility of the medical profession in the field of assisted reproduction. And who can blame the media for such conclusions?

The physician heads what on the website is called The Fertility Institutes, with one confirmed location in Encino, CA. Although his clinic offers comprehensive infertility services on its website, it is apparent that gender selection defines the identity of this clinic, which calls itself the world’s largest provider of sex selection IVF cycles, with thousands of patients having chosen the center’s services from all over the world.

Gender selection through preimplantation genetic diagnosis (PGD), first of all, necessitates an IVF cycle. Therefore, when we realize that, according to the latest CDC data, this “largest sex selection center in the world” has done only 127 cycles of fresh IVF and 38 egg donation cycles, the claim starts to fall apart. This means that, even assuming that all IVF cycles at this institute were done for the purpose of sex selection (a not very likely assumption), it is difficult to understand where the thousands of sex selection cycles were done (of course, with 100% accuracy!), claimed by its official website.

In most of its currently used clinical applications, PGD is a highly complex technical procedure, used to prevent specific genetically inherited diseases in offspring. A wider application of PGD, in an attempt to improve IVF pregnancy rates and reduce miscarriage rates, by selecting chromosomally normal embryos has, as we have extensively written about in many publications, been proven to be mostly ineffective. Indeed, in an older patient population, the additional trauma of embryo biopsy required for PGD may actually reduce IVF pregnancy rates (Gleicher et al., Fertil Steril 2008;89:780-8).

The concept that, assuming the technical ability to affect cosmetic traits reliably, masses would suddenly flock towards PGD to produce blond, blue-eyed offspring, is just as unrealistic as the other fantasy propagated by the institute’s website’s—of thousands of alleged sex selection cycles. Only few couples choose gender selection, even though it has become quite freely available in the U.S (CHR has offered the service for years). Even fewer would choose PGD for cosmetic reasons. You have to give it to the guy, however; he really pulled off a remarkable P.R. stunt!

Increased Risk of Birth Defects after IVF?

After over 3 million IVF births worldwide proved the initial concerns about “freakishly malformed babies” (Peggy Orenstein, New York Times, July 20, 2008) wrong, suddenly the specter of a higher birth defect rate following IVF, once again, became a favorite media topic in March.

It all started with one study published by investigators from the National Center on Birth Defects and Development Disabilities, Centers for Disease Control and Prevention in Atlanta (Reefhuis et al., Human Reprod 2009;360-6), in which the authors reported increased rates of septal heart defects (OR =2.1; 95% CI 1.1-4.0); cleft lip with and without associated cleft palate (OR 2.4; 95% CI 1.2-5.1); esophageal atresia (OR=4.5; 95% CI 1.9-10.5) and anorectal atresia (OR = 3.7; 95% CI 1.5-9.1). On first glance, these data appear impressively significant. Reviewed in more detail, however, significant questions arise about their scientific validity.

Among other issues, the study compared infertile women treated by IVF with women who spontaneously conceived and, therefore, quite apparently did not suffer from infertility. It has been known forever that women requiring infertility treatments give birth to children with slightly increased risks towards birth defects in comparison to spontaneously conceived offspring from fertile couples. Any study attempting to determine whether IVF/ART increases birth defects, therefore, should compare IVF cycle outcomes to outcomes of other infertility treatments. The study format chosen by Reefhuis et al cannot differentiate between effects of infertility in general and effects of IVF on risk towards congenital abnormalities.

In recent years, based on a tiny number of cases, a special group of extremely rare congenital birth defect risks (such as Beckwith-Wiedermann syndrome, Angelman syndrome and retinoblastoma) has been suggested to be directly associated with ART. Whether there even is a genuine association between ART and these disorders is still unproven and has recently been questioned by a group of investigators from the Reproductive Biology and Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, in Bethesda. Because such imprinting disorders are rare (< 1:12,000 births), the authors currently recommend against routine screening for these disorders in children conceived with ART (Manipalviratn et al., Fertil Steril 2009;91:305-15).

Unfortunately in medicine, poor data and/or incorrect interpretation of data so often lead to poor clinical decision making and, even more unfortunately, to wrong authoritative recommendations. (Readers might recall the old fear about the alleged cancer risks associated with fertility drugs.) The above cited paper of Reefhuis et al is no exception. Perhaps not surprisingly, the United Kingdom’s by now notorious Human Fertilization and Embryology Authority (HFEA) is, according to reports in British and U.S. media, updating its IVF guidance based on this single, obviously flawed, paper by Reefuis et al. It appears that HFEA is out to prove to the rest of the world how bad and illogical government interventions into daily medical practice can be!

We are convinced that, beyond extremely minor direct risks from ART along above-outlined possibilities, appropriately conducted studies will soon debunk the allegedly increased risks towards birth defects in association with IVF, just as properly controlled study years ago erased the anxiety over ovarian cancer risks associated with fertility drugs.

IVF is an extremely safe procedure. Introducing baseless fear into already stressed-out infertile patients seems not only unwarranted, but almost cruel. Infertile couples should not have to worry about speculative risks!


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Letter from a Patient: DHEA Baby Down Under

We are pleased to update the story of an Australian couple previously printed in the VOICE. After turning 40 and finishing two failed IVF cycles, “Nancy” chanced upon the CHR website where she learned about the possibilities of DHEA. Nancy contacted CHR, who specified DHEA treatments that were supervised by her local “down under” clinician. She soon achieved a successful pregnancy, which is where our first report left off.

She has since given birth to a healthy 7 lb. 1 oz. boy and the new family is doing fine. “We are so thrilled,” she said. “Thank you, CHR, for your work with DHEA as without it we wouldn’t have our dear little fellow.”
- "Nancy and Gene," New South Wales, Australia

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CHR in the Media

As we have noted elsewhere in this issue of VOICE, 2009 continues to be an exciting year for CHR when it comes to media attention. Various media sources, both domestic and international, called on Dr. Gleicher’s expertise in the ART field as one outrageous event after another unfolded surrounding IVF. This included the Chicago Tribune, CNN, and a radio station in New Zealand. A list of Dr. Gleicher’s media appearances are available here.

Dr. Kutluk Oktay, who heads the Institute for Fertility Preservation (a division of CHR), was also consulted when the news broke out that a team of Chinese researchers made a breakthrough discovery with clinical implications in fertility preservation (Zou et al, “Production of offspring from a germline stem cell line derived from neonatal ovaries.” Nat Cell Biol. 2009 Apr 12. [Epub ahead of print]). They implanted germline stem cells harvested from the ovaries of adult mice into ovaries of sterlized mice. The recipient mice successfully produced offsprings, which Dr. Oktay called “perhaps the most significant finding in reproductive biology in the last 50 years.”

Dr. Oktay, unfortunately, will have to concentrate on his practice at New York Medical College and will leave CHR after July. Dr. Gleicher will assume responsibility for fertility preservation at CHR as of this point.

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Contact Us to share your experience

Would you like your CHR experience featured in a future edition of The Voice? An ongoing open call has been established for all CHR patients interested in sharing their experience, or simply featuring pictures of their bundles of joy. If you are interested in submitting your experience or pictures, please e-mail us.

CHR Voice Contact Information
Editorial Office
Center for Human Reproduction
650 West Lake Street
Suite 200
Chicago, IL 60661
FAX: 312.876.1804
Phone: 312.876.1505

The CHR Voice welcomes contributions. For more information, please contact the Editorial Office at the above address.

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