CHR Update April 2006

AN UPDATE ON DHEA

Our work with DHEA is continuing and there is, indeed, further progress to report. Let us start with developments at CHR: A study, comparing a good number of IVF cycles, in the same women, before, and after treatment with DHEA, has been accepted in the journal Human Reproduction and should be available, at least in electronic format, within a few weeks. As we already reported on our website in prior updates, this study showed significant improvements in egg and embryo numbers, but even more importantly, significant improvements in egg and embryo quality.

We have in the meantime also completed a carefully controlled, so-called, case-control study, in which we not only wanted to determine, once more, the impact of DHEA on pregnancy chance, but, this time, also on the timing of occurrence of pregnancy. In other words, we not only wanted to confirm that DHEA, indeed, increases the chance of conception, but also wanted to determine whether it impacts how quickly somebody conceived.

In this study we compared close to 100 women who, before going into IVF, were first placed on DHEA to an almost identical number of carefully matched historical controls, who, after presentation to CHR, had been immediately directed into IVF. We then compared the time it took both groups of patients to conceive
and, of course, which of the two groups conceived more pregnancies.

The results were quite dramatic: Not only did DHEA patients conceive significantly more pregnancies than controls, but even though DHEA patients were, of course, delayed from entry into IVF by a few months, they still conceived significantly quicker and that difference was apparent within two months from presentation. Considering our prior recognition of the high spontaneous pregnancy rate on DHEA, we really were not surprised by these findings but it was, nevertheless, nice to see our assumptions confirmed by a rather rigorous statistical evaluation.

Dr. Gleicher will be presenting a DHEA Update on June 19, at the upcoming meeting of ESHRE (the European “Fertility Society”), in Prague, Czech Republic. In addition, we have also submitted a manuscript for publication.

There is, however, more to report on DHEA: You may recall that Dr. Gleicher in November of 2005 was invited to present the CHR’s DHEA data on a lecture tour through Japan and Taiwan, at the Annual Meeting of the Japanese Fertility Society. His presentation must have made an impression because, being once again invited to lecture in Japan, just a few weeks ago in May of this year, at the Annual International Ovarian Conference, there were already two abstract presented by Japanese investigators on the successful use of DHEA in women with diminished ovarian reserve. Moreover, Dr. Gleicher was informed by his hosts that a number of Japanese medical schools had formed a consortium for a multi-center study of DHEA, which will be kicked off in the very near future.

We are, of course, very happy about these developments because the more centers start investigating DHEA, the quicker we will have a comprehensive understanding of its actions on the aging ovary.

PREMATURE OVARIAN AGING (POA) AND POLYCYSTIC OVARIAN DISEASE (PCO) Program

PCO is one of the most fascinating medical conditions in our specialty. It, therefore, has attracted us as a research topic for many years. Over the last year this interest has peaked because we have, increasingly, started to view PCO as the opposing extreme to premature ovarian aging (POA): While POA-affected women develop ovarian resistance and early menopause, PCO-affected patients recruit unusually large oocyte numbers and are now believed to experience late menopause.

POA can, therefore, be seen as a shift of the physiologic ovarian aging curve towards the left (i.e., younger age) and PCO can be perceived as the opposite, – a shift of the aging curve towards the right (i.e., older age).

We have been exploring this concept in our research efforts in a number of ways. In a previous UPDATE we reported that Yale University fellow, Andrea Weghofer, MD, Ph.D., in working with Drs Gleicher and Barad, determined that POA patients do not demonstrate the increase in oocyte and embryo aneuploidy (i.e., chromosomal abnormalities) which are seen with physiologically aging ovaries. We also noted that this observation explains why women with POA do still have excellent pregnancy chances, if properly stimulated (a publication from our Center on this topic is currently in print in Fertility and Sterility; see also below).

Since then, Dr. Weghofer, in collaboration with Drs Gleicher, Barad and investigators from St Barnabas Medical Center, and Reprogenetic Laboratories, in Livingston, N.J., determined that PCO patients also demonstrate entirely normal rates of aneuploidy. In other words, she was able to demonstrate, once more, the “symmetrical” behavior of POA and PCO.

POA AND ADRENAL DISEASE?

PCO has for many years been known to be associated with adrenal gland abnormalities in the production of steroidogenic enzymes. That POA patients may also show similar adrenal defects has, however, so far been unknown.

We previously reported in one of our UPDATES on a POA patient (from the outside of CHR) who, graciously, had made us aware of her very detailed medical history, suggestive of an adrenal enzyme defect, that had led to low DHEA levels. Once her DHEA had been substituted, she, once again, spontaneously ovulated and, after long-standing infertility, conceived by IVF, and delivered a healthy child. This patients has since informed us that, after instigating DHEA again, she has conceived again and is currently in advanced stages of a second pregnancy.

This patient’s experience led us to the idea to investigate the adrenal function of POA patients. Once again, our current thinking about POA and PCO as opposing extremes of the ovarian aging process, also supported such an investigation in consideration of known adrenal enzyme defects in PCO patients.

We have so-far investigate approximately 15 consecutive POA patients and have, indeed, found that, in a large majority of cases, ACTH stimulation tests (like in PCO patients) are abnormal. The findings we see are suggestive of partial adrenal steroidogenic enzyme defects. To rule out any genetic contribution, we have in collaboration with Robert Wilson, Ph.D., from the Molecular Biology Laboratory of the Department of Pediatrics at Mount Sinai School of Medicine, by molecular techniques attempted to detect the most frequent genetic adrenal enzyme defect in a small number of women with POA, but have failed. This then suggests that the enzyme defects we are detecting in POA patients by ACTH stimulation are not inherited in the traditional way, but may be acquired.
(A paper describing this work is currently being prepared for publication.)

We, of course, so-far do not know how these adrenal enzyme defects in steroidogenesis occur in women with POA. Our current working hypothesis, as reviewed in our last UPDATE, is that they are autoimmune in nature. We, indeed, have a large study underway, in which we are looking closely at patient and family histories of POA and control patients. If POA, indeed, were to be autoimmune in nature, one would expect a higher prevalence of other autoimmune conditions in POA patients and their families.

Look for future UPDATES in following this exiting story. We are by now quite convinced that our research will greatly enhance our understanding of POA and PCO. As soon as we will know, you will know!

RECENT PUBLICATIONS

A floury of four papers from CHR was recently published almost concomitantly.

A paper by Drs Gleicher and Barad, entitled “An evolutionary concept of polycystic ovarian disease: does evolution favor reproductive success over survival?” appeared recently in Reproductive BioMedicine Online (2006; 17:587-9)

Polycystic ovarian disease (PCO) is by many considered the most frequent cause of female infertility and has, therefore, always been of considerable interest to investigators at CHR. This interest is reflected in this paper, where Drs Gleicher and Barad argue that there must be an evolutionary benefit to PCO if it has survived as such a prominent condition in mankind for such a long time.

Three other papers have appeared in the medical journal Human Reproduction, though, so far, only in electronic format, with their printed versions to appear over the next few months. The first such paper, again by Drs Gleicher and Barad, is entitled “The relative myth of elective single embryo transfer.”

In this paper Drs Gleicher and Barad question the current rush in the medical literature towards single embryo transfer as “unpractical” and argue, that single embryo transfer, while a very desirable option in qualified patients, will in the U.S. find only very limited application because only very few patients truly qualify as candidates for such an approach.

Another paper, entitled “A formal comparison of the practice of assisted reproductive technologies between Europe and the USA,” by Drs Gleicher, (Andrea) Weghofer and Barad, for the first time in systemic fashion points out the remarkable difference in pregnancy outcome between the European and U.S. experience. Since a large part of Europe, mimicking the mandated reporting of IVF outcomes in the U.S., has now started to report on continent-wide outcomes, it has become feasible to formally compare IVF outcomes on both sides of the Atlantic. As anecdotally, has been known for a while, European pregnancy rates are far inferior to those in the U.S., and this paper not only points out this fact, but also tries to explain what the causes for this discrepancy may be.

Finally, Drs Gleicher and Barad also published a paper, entitled “Unexplained infertility: Does it really exists?” In this article they argue that the diagnosis of unexplained infertility should be abandoned because it, in a practical sense, only serves to confuse, and is used as an excuse for shoddy diagnostic evaluations of infertile couples. Drs Gleicher and Barad furthermore argue that most cases of so-called unexplained infertility represent failures to diagnose four conditions: endometriosis, tubal infertility (mostly distal tubal and peritubal disease), premature ovarian aging, and immunologic infertility.

As noted in the DHEA update above, one of our DHEA papers is “in press” at Human Reproduction. Moreover, Drs Gleicher and Barad have another manuscript, describing the successful use of microdose agonists in women with diminished ovarian reserve “in press” in Fertility and Sterility. Both of these papers are, therefore, also expected to appear in print in the near future.

In addition, an approximately half a dozen additional manuscripts have been submitted and are currently under review and, as always, we, of course, are working on additional materials for publication.

These are exiting times at CHR, and we thank you for your interest in our work.

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.