Factoring attrition into natural and ART-based human fecundity

Knowing is not enough; we must apply.

Willing is not enough; we must do.

Goethe.

Acquiring and implementing new knowledge in any endeavor aimed at improving the human condition is to be commended. And given the evolution of the biomedical research enterprise over the past 5 decades, the acquisition of basic knowledge from model systems, especially mammals, has in one sense contributed measurably to both the insights and reservations adopted in the pursuit of diagnosing and treating human diseases. Add to this the “wonderful world of stem cells and regenerative medicine” for drug screening of “oids” and generating all manner of organ and tissue lookalikes, we arrive at a juncture that in some circles might suggest that the cure is imminent.

In reproductive medicine, having the willingness to do good for patients has never been the problem. Facing the odds against which all the processes invoked to achieve and sustain pregnancy is quite another matter.

This month we tackle the problem of attrition as manifest directly and indirectly in the practice of human ART. And confounding any treatment of a subject like this is both the natural and unnatural ways in which we seek to live in a world of plenty—as some would say “the more the merrier.” Having more of a commodity is not an uncommon a principle in biological systems given the degree of redundancy, repetition, and replication manifest in living systems.

Comparing the way Mother Nature has decided to effect fecundity in humans to what we do in the ART world begs the question of just how many eggs, sperm, or embryos are needed to bring about the birth of healthy offspring for our patients. With the millions of embryos in ART databases now in hand, much has been gleaned about the nuances of  early human development that never could have been fully appreciated before.

For example, the contemporary research bandwagon continues to shed light on both the nature and extent of how challenging things are getting out of the gate just after fertilization with any number of risky maternal and paternal behaviors setting the stage for genetic liabilities [1]. Good thing in the minds of many and the land of plenty that strategies evolved to overcome the natural monovular property of hominids ushering in controlled ovarian stimulation (COS) to obtain as many oocytes as possible with which to prepare a ready supply of zygotes for our patients awaiting the results of the “fert check.” Unfortunately for all, as was realized many years ago already, a small fraction of the oocytes retrieved yield a child emphasizing the degree of attrition that must exist along the ART journey [2]. With the growing utilization of single embryo transfer and methods for selecting, or deselecting, embryos for transfer hopes are indeed high for seeing an improvement in the oocyte to baby conundrum first raised by these provocative studies.

The uncertainties underscoring why so few of the many oocytes retrieved are capable of post-insemination development are resolvable to a certain extent by recognizing and accepting that the human meiotic spindle is unusually fragile, unlike those of most other mammals, and as noted above, the cell cycle machinery inherent in human oocytes and embryos appears to manifest itself in a negative fashion given the challenges posed by conventional ART technology as currently practiced [3]. This is not to say that there is a dimension of our ART practices that could someday be recapitulated in the form of much less attrition, a most welcome prospect for our patients anxiously awaiting a phone call from laboratory directors the day after retrieval.

But getting back to our collective apetite for more materials to start with, it is interesting to note that during the advent of COS, direct descendants of the Edwards and Steptoe efforts found little positive impact of COS on clinical outcomes forecasting, in a way, the very question that has been echoed for years: Is more better [4]? Mother Nature in her infinite wisdom must have contrived some reason for endowing human ovaries with a plentiful supply of primordial follicles from which to draw upon a select few to engage in the prospect of fertilization and beyond. As suggested by others [5], our efforts to improve on fecundity have already been notable despite the natural course of attrition over the reproductive lifespan of women. But what more can be done? Surely as noted last month in our focus issue on Fertility Preservation, at the very least, our field is poised to unravel the causes and adaptations that must have evolved within the context of human reproduction to establish attrition as Nature’s own way to exercise selectivity in the demanding and essential processes aligned with establishing and maintaining pregnancy.

In the end, we must accept that while the numbers game is in play, in parallel with the age factor, to exact the real source of the link between gamete and embryo quality, for both the male and female, a concerted and painstaking effort must be realized to define the cellular and molecular bases that drive both the amplification and the demise of so many gametes hoping to engage in things to come.

Attrition in some cases may be causative to higher goals, as recent research on the ovary suggests [6], something that our neuroscience colleagues have known since the times of Santiago Ramón y Cajal.