Practice Of Human ARTs Research Articles

Forgotten fluids of the reproductive tract

Forgotten fluids of the reproductive tract

When looks are deceiving—the challenge facing embryo quality prognosticators

The quest for biomarkers of embryo quality is as seasoned as the practice of human ARTs itself. Reaching back into the annals of IVF reminds us of the attempts of the late Bob Edwards and his progeny during the 1980s that placed the property of fragmentation at the disposal of budding embryologists charged with identifying those embryos most suitable to transfer—and, hopefully, endowed with the most potential to give rise to a term pregnancy. As Bob showed, not so reliable was this admittedly “ugly” identifier as a predictor of implantation, let alone pregnancy. And then there were the primordial and laudable efforts of Lucinda Veeck and her colleagues to catalogue the entire range of morphological variation in oocytes, sperm, and embryos proffered to prognosticators for the next decade of human ARTs, one that brought with it measurable advances in ovarian stimulation and ICSI, placing “in the dish” many more embryos to transfer to the delight of patients and clinicians than could have been anticipated 10 years before. But, truth be told, embryo selection remains a vague and frustrating exercise, heightening the need for something less subjective and more objective even in the face of an “embryonic embarrassment of riches.” A turning point in this field of endeavor came from the pioneering efforts of the late Lynette Scott. Her passion and observational talents were harnessed through a series of papers describing the details of pronuclear development, and their attendant dynamics, providing to the ART community yet another landscape with which to discriminate between those embryos most desirable for transfer. Bearing in mind that her insights came at a time when discussions as to the optimum stage for transfer presaged the introduction of media extending the developmental window to blastocyst, pronuclear staging filled an important gap in our understanding of the earliest stages of human development. She also was among the first to deploy time-lapse imaging, convinced that cellular behaviors at the one-cell stage might someday be linked to outcome measures consistent with a term pregnancy. Now comes a report from the laboratory of Dr. Sangita Jindal taking aim at the utility of pronuclear scoring as a biomarker for pregnancy outcome (this issue JARG, Berger et al., 2014, “Embryo quality but not pronuclear score is associated with clinical pregnancy following IVF” DOI 10.1007/s10815-013-0162-3). Using more contemporary biomarkers of embryo quality such as cell number, fragmentation, and blastomere symmetry, the results clearly indicate that the application of pronuclear scoring offers no additional benefit over the use of the accepted measures cited above in terms of clinical pregnancy rates in Day 3 transfers. While putting to rest one approach to embryo scoring, and validating the use of criteria in Day 3 embryos firmly entrenched in the formative events of compaction and cavitation, this work also sets the stage for a new perspective on embryo quality assessment consonant with extending the culture period to Day 5 or 6 for embryo transfer. Why? Because along with extended culture comes the opportunity to track and deconstruct the details of individual preimplantation embryos under the watchful “eyes” of time-lapse imaging while cohorts of concepti make their merry way to the day of transfer content in their isolation in microdrops of media designed to recapitulate the female reproductive tract. It is undeniable that the introduction of dynamic imaging brings an analytical array of benchmarks to the prognosticators’ playbook. It is far less apparent to what extent the “criteria under development” will indeed offer more reliable and accurate indices of embryo quality. Here at JARG, we remain mindful of the historical traces of gamete and embryo evaluation that may at the time have satisfied the needs of embryo selection but in the end offer little more when it comes to predicting whether a clinically significant event will ever take place. While as a community of clinicians and scientists eternally optimistic that the perspective of time-lapse imaging will bear fruit as a predictive tool, “proof of the pudding” has yet to be realized. We encourage out readership to maintain focus in the pages of JARG as this next phase of embryo quality assessment matures into what will hopefully become a useful tool.

Tales of a spermatological variety—finding master right

Tales of a spermatological variety—finding master right

Reproducing the most natural way-the changing face of human ARTs

Reproducing the most natural way-the changing face of human ARTs

Meeting organizers welcome

It is our honor and privilege to welcome you to the 6th meeting of ISMAAR. Planning for the follow-up to our meeting in May of 2012 in Denmark has involved a concerted effort on the part of our members, the local organizing committee, and the leadership of ISMAAR. We express our deepest gratitude to all who have contributed to making this an outstanding venue and program that is sure to move our goals closer to reality in the coming years. But the work is just beginning if our international congress is to achieve its objective. ISMAAR is committed to changing the global landscape of human ARTs. Our program this year highlights many of the advances that have taken place in basic and clinical science but without your engagement and participation, the momentum we now appreciate will fall short of our intended purpose. The experts we have convened on this special occasion are just that-international leaders in their respective disciplines who will share their insights and practices with you over the course of several days filled with questions that remain and controversies yet to be resolved. Your role is to take full advantage of these offerings in a forum of open discourse and discussion that will make this meeting one to remember for years to come, and one that will allow ISMAAR to take one step closer to realizing our dreams for our patients and the practice of human ARTs. So it is, in the spirit of friendship and comraderie that we extend our warmest welcome to our participants, speakers, and honored guests and trust that you take with you memories of our 6th meeting in Nanjing that will endure for years to come.

Searching for answers to the riddle of ovarian aging

Searching for answers to the riddle of ovarian aging

Knocking heads with viscosity: new insights into the bioenergetics of sperm motility

Among the marvels of human reproduction, au naturel, is how a spermatozoan negotiates the perilous journey through the female reproductive tract. While a small and select number of sperm may populate the ampulla of the Fallopian tube, the chosen ONE—at the expense of its compatriots—will be distinguished by having confronted and overcome that last series of barriers before fusing with the oocyte plasma membrane. Having the “right stuff” to make this happen has been within the purview of spermatologists and the few who dare to venture into the wonderful world of reproductive tract secretions and the like. But only recently have advances been made that begin to uncover the unique properties of sperm, which empower them with the ability to withstand and progress through the global climate change that anticipates fertilization on a cellular scale. This issue of JARG brings to the forefront two features of the process of fertilization that have been lost within the PubMed archives. An article by RHF Hunter and colleagues revisits the problem of the female reproductive tract microenvironment from a comparative perspective, reminding us that the challenges imposed on human sperm are not unlike those faced by other species that have made the evolutionary commitment to internal fertilization. This paper reveals a biophysical dimension of environmental flux involving changes in viscosity, viscoelasticity and temperature, as sperm transit from one microenvironment to the next. One cannot help but conclude that along this not-so-merry sojourn, sperm must be capable of shifting gears in accordance to the kinds of environmental cues encountered—a more salutatory motility behavior that is in sharp contrast to the relatively mild selection steps taken during sperm preparation for IVF or ICSI. Continuing along the theme of nature versus ART-dependent nurture, Dale and DeFelice (Polspermy prevention: facts and artifacts) extend such a comparative viewpoint a bit closer to the subject at hand: fertilization. In challenging conventional notions regarding the fast block to polyspermy, in particular, they emphasize that almost all of the knowledge we have for the mechanisms underlying monospermic penetration derives from studies on animal models that bear little resemblance to the human condition. Moreover, considering what has evolved in the practice of human ARTs, where virtually all natural interfaces that would be encountered by a fertilizing sperm have been eliminated (cumulus, zona), they posit that, where fertilization should be occurring on the human oocyte has become a crap shoot! That is, if there is a preferred and optimal place for sperm entry and egg activation, this is surely not the case when the ICSI pipette is aimed at anywhere but the site of the meiotic spindle. Food for thought, for sure, and an idea that is not likely to gain support until the experiments can be performed on human material. Both of these articles bring our readership up to date at a time when questions about the long-term consequences of ICSI continue to be raised and the recurring ballad of how to choose the best embryo seems not to wane. In the end, the imperative to understand and more effectively treat male infertility is loud and clear: Motility parameters are readily monitored in the andrology lab and seeking explanations for poor motility, at a genetic and physiological level, will hopefully bring our diagnostic and treatment strategies to a heightened level. To this end, I would like to draw your attention to an example of a basic science breakthrough that impacts our understanding of male infertility and offers new avenues for a male contraceptive development. A recent study published by Jimenez and coworkers (2011, PNAS 108:644–649; www.pnas.org/cgi/doi/10.1073/pnas.1016902108) identifies a novel isoform of the Na,K-ATPase (ATP1A4) that is essential for male fertility in mice. In addition to their infertility, the study goes on to show that sperm from animals lacking this isoform fail when used in IVF, and exhibit decreased motility—as expected, given the essential role of this plasma membrane transporter in ion transport. This same group has extended its studies to show that, by inserting a copy of the rat gene for the ATP1A4 isoform into the mouse genome, the mouse sperm exhibited enhanced total and progressive motility (Jimenez et al., 2011, Biol. Reprod. 84:153–161 DOI 10.1095/biolreprod.110.087064). Strikingly, analysis of the re-engineered sperm showed that the hyperactivated motility typical of sperm capacitation is also increased in both total and progressive motility. The significance of studies like those of Jimenez et al. is that they bring our understanding of sperm physiology more closely in line with the complexities of motility that are required to achieve successful fertilization. As the next decade of human ARTs continues to unfold, we look forward to discoveries like this, to guide our efforts in the diagnosis and treatment of male infertility.

On the matter of Krogh’s principle

On the matter of Krogh’s principle