CHR Update October 2012

A very busy month is ahead of us, with the Annual Meeting of the American Society for Reproductive Medicine (ASRM), this year in San Diego, smack in the middle of the month, where CHR investigators will be presenting a few papers. This at a time when CHR is clinically busier than ever, and our research staff receives offers to collaborate with other researchers almost on a weekly basis!

CHR Research

Exciting things are happening all over the research front: Likely, one of the most important papers from CHR was just published late in September in the prestigious PLoS ONE on-line medical journal (Weghofer et al, 2012;7:e44753). In collaboration with two Austrian research centers at Vienna and Graz Universities, CHR researchers reported a result, though highly technical-sounding, has potentially major diagnostic and therapeutic implications far beyond infertility.

The so-called “BRCA-paradox” refers to the unexplained observation that BRCA1/2 gene mutations in embryonic tissues inhibit cell proliferation, while in some cancers they do exactly the opposite: cause cancer growth.

CHR investigators now appear to have solved this paradox in the PLoS ONE paper: women with BRCA1/2 mutations practically exclusively demonstrate one specific kind of another gene, a so-called “low” sub-genotype of the FMR1 gene. Such low sub-genotypes are found in approximately 25% of all women. The only likely explanation for almost 100% of women with BRCA1/2 mutations having low FMR1 is that, without it, BRCA1/2 mutations are embryo-lethal.

Embryo lethality of BRCA1/2 would not surprise since, as noted above, BRCA1/2 mutations have antiproliferative (i.e., anti-growth) properties. But how come BRCA1/2-positive embryos with low FMR1 sub-genotypes survive? Again, there is only one likely explanation: the low FMR1 gene “rescues” the embryo from lethality and, likely, does so by inhibiting the anti-proliferative effects of BRCA1/2 mutations.

As a consequence, we end up with humans who are carriers of BRCA1/2 mutations and the low FMR1 gene. Now remember, the low FMR1 gene, likely, blocks the anti-proliferative effects of BRCA1/2 and causes the opposite: proliferation! In adults, this would lead to excessive cancer prevalence in at-risk tissues, and, voila, we have the explanation for how BRCA1/2 can be anti-proliferative in embryonic but proliferative in breast and ovarian cancer tissues, the “BRCA-paradox.”

For the longest time this increased cancer risk has been attributed to BRCA1/2 mutations. Now it appears that these BRCA1/2 mutations, being anti-proliferative, are actually protective of cancer. It, therefore, is really the low FMR1 sub-genotype, which inhibits the anti-proliferative effects of BRCA1/2, that appears to cause these cancers. They just exclusively occur in BRCA1/2 carriers because, without a low FMR1, a BRCA1/2 embryo would, simply, not survive.

If confirmed by follow-up studies, these findings, of course, can have enormous significance for diagnosis, potential prevention and treatment of BRCA1/2-associated cancers. BRCA1/2-associated cancers are especially frequent amongst Ashkenazi-Jewish women. CHR was already approached to license a pending FMR1 patent.

NIH Grant Application

It has been quite a while since CHR submitted a research grant application to the National Institutes of Health (NIH). Now, as part of CHR’s collaboration with Rochester University School of Medicine, and with Aritro Sen, Ph.D., Visiting Assistant Scientist at CHR, as Principal Investigator, CHR is part of a comprehensive research grant, which attempts to further investigate the effects of androgens on ovarian follicle maturation. Considering how few grants NIH funds these days, we will need a little bit of good luck!

Can CoQ10 Recharge the Power Plant of Eggs?

Researchers in various areas of medicine have been showing increasing interest in damages induced by oxidative stress. Infertility is no exception, with researchers in female and male infertility starting to demonstrate increasing evidence that the prevention of such damage may be possible. With Vitaly Kushnir, MD, joining CHR, we have gained considerable expertise in this area, since he has been working for some time on the question of how oxidative stress affects ovaries. We, therefore, thought it was time to update you, our reader!

Egg quality is closely associated with number and function of mitochondria, the power plants of the cell. The largest cells in the body, oocytes contain, by far, more mitochondria and mitochondrial DNA (mtDNA) copies then any other cell.

When in meiosis, half of the chromosomes are removed from the egg in form of the first and second polar bodies. To support transcription and translation, the egg requires substantial energy. ATP provides this energy from oxidative phosphorylation, generated through the mitochondrial electron transport chain. Deficiency of electron transport chain proteins depletes cellular ATP and compromise spindle formation, checkpoint control and chromosome alignment. Spindle alterations may result in aneuploidy (chromosomal abnormalities), failure of implantation and early miscarriage. Additionally abnormal mitochondrial activity and low ATP may alter embryo cell division and development.

Evidence suggests that quality deterioration in aging oocytes primarily results from disorders of the meiotic spindle formation and spindle malfunction. It has been suggested that accumulation of mtDNA mutations and deletions are associated with loss of mitochondrial function. mtDNA damage may accumulate for years in a dormant follicle, prior to recruitment of an egg. mtDNA is located in close proximity to the electron transport chain, where reactive oxygen species are generated. Because mtDNA lacks the protection from repair mechanisms of histones available to nuclear DNA, mtDNA is relatively vulnerable to mutagenesis. Thus, the mutation rate of mtDNA is ten times greater than that of nuclear DNA. Because mtDNA lacks noncoding introns (i.e., has no “extra” genetic material that is not used for anything), it is also more likely for any given mutation to result in functional alterations of the cell.

Indeed, the so-called “common deletion” of 5,000 base pairs, almost a third of the mtDNA genome, is frequently seen in unfertilized oocytes and oocytes from older patients. Moreover, oocytes from women with ovarian insufficiency have been reported to contain lower mtDNA copy numbers than those of women with normal ovarian reserve.

The same applies to granulosa cells, which surround the oocyte during maturation and supply the oocyte with nutrients. Granulosa cells in older women have fewer normal mitochondria. Mitochondrial distribution in oocytes and early embryos is closely correlated with developmental competence. Data from animal models indicates decreased ATP content and number of mitochondria in aged oocytes (www.ncbi.nlm.nih.gov/pmc/articles/PMC3169682).

Mitochondria, thus, appear to play a major role in a variety of mechanisms that ultimately determine oocyte quality and quantity. The basic concept behind supplementation with mitochondrial nutrients is, therefore, to optimize energy availability for chromosomal disjunction and, ultimately, improve oocyte quality by decreasing the risk of aneuploidy. This, theoretically, should lead to improvement of pregnancy outcomes, particularly for women in their later reproductive years or those with premature ovarian aging (POA).

Mostly based on animal data, many experts currently consider coenzyme Q10 (CoQ10) the most promising antioxidant to achieve these goals. Rigorous studies in infertile women, however, are still lacking. Antioxidants have much more extensively been studied in men.

Between 30% and 80% of male subfertility is considered due to the damaging effects of oxidative stress on sperm. A recent Cochrane review of 34 trials with a total of 2,876 couples concluded that antioxidant supplementation in subfertile men appears to improve pregnancy and live births rates in couples undergoing ART cycles. Of equal importance, none of the 34 trials reported any evidence of harmful side effects of such antioxidant therapy in men.

CoQ10 transports both electrons and protons into the mitochondria to maintain their membrane potential, and also drives ATP synthesis. CoQ10 levels physiologically decline with advancing age in all tissues. CoQ10 supplementation, therefore, has been shown effective in the treatment of a variety of disorders characterized by significant mitochondrial dysfunction, including congestive heart failure, hypertension, diabetes, Friedreich’s ataxia, Parkinson’s disease, migraines, macular degeneration, and asthenozoospermia (abnormal sperm).

Recommended CoQ10 supplementation dosages range between 100 and 3,000 mg/day. Interestingly, adrenal glands and ovaries show remarkable uptake of CoQ10, and nearly double their initial concentrations of CoQ10 with supplementation. We find this fact of particular interest, because we, increasingly, have come to see POA as a combined adrenal/ovarian insufficiency. One, therefore, could hypothesize that CoQ10 supplementation may find a special place in association with POA.

Supplementing in vitro culture with CoQ10 has improved the quality of bovine embryos. Preliminary data from Dr. Robert Casper’s group in Toronto, Canada, on aged mice indicates that pretreatment with CoQ10 before ovarian stimulation improves mitochondrial activity and number of oocytes. Long-time readers may recall that CHR collaborated with this group in the past on a project of dehydroepiandrosterone (DHEA) supplementation in older mice.

Dr. Casper is preparing a multicenter clinical trial evaluating the efficacy of CoQ10 supplementation in improving oocyte quality in older women undergoing fertility treatment. CHR is planning to participate in this trial. Stay tuned for more to come on CoQ10!

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