Mechanisms of infertility: does diagnosis dictate therapy?

Infertility care logically involves a firm grounding in reproductive biology, endocrinology, genetics, and cellular and molecular physiology. Given this dependence on traditional scientific foundations, it is surprising that the treatment of infertility is so often laden with opinion and superstition. Perhaps the reason for this irony can be found in the behavioral and mathematical sciences. First, it is no surprise to anyone that reproduction is fundamental to our sense of self. Being unable to conceive when and with whom one wants may be experienced as a psychologic threat akin to death. This emotional vulnerability predisposes to magical thinking and the stages of grief, including depression and bargaining. Second, conception and gestation are governed by probability, that is, the rules of chance. When outcome is probabilistic, humans tend toward magical thinking as a means of gaining control over uncertainty. An outcome that is both psychologically important and uncertain inspires mysticism and superstitious behaviors in patients and physicians alike.

One of the objectives of this collection of articles is to demystify infertility by focusing on what is known about its causes. In an ideal world, cause dictates, in a straightforward manner, intervention. The more we understand about underlying pathogenetic mechanisms, the greater should be our ability to intervene in a rational manner. The last article outlines what it takes, in terms of study design and statistical considerations, to determine the efficacy of an intervention or to compare interventions. We have been urged to practice “evidence-based” medicine. Although important information is derived from clinical trials, it is helpful to remember that there are other types of evidence that contribute to the best clinical practice. I like to think of the practice of medicine as continuously improving through the “cycle of evidence”: mechanistic insights drive new interventions that need to be tested in clinical trials, and clinical trials suggest new questions to be answered by mechanistic studies.

Current infertility interventions fall into categories based on the limits of our diagnostic armamentarium and therapeutic options. Ideally, we aim for cures and outright corrections. However, because this is often not completely possible, the second line of defense may be needed, which is to increase the odds by increasing gamete number and physical approximation of gametes. These latter therapies might be best viewed as “enhancements” of probability. When all else fails, we offer substitutions. In the past, this took the form of adoption of infants. Now our technology allows for gamete and embryo substitutions. Although it is a general impression that the availability of these options relieves the psychologic burden and suffering of infertility, in truth little attention has been paid to the actual psychologic consequences of treating or not treating infertility.

What would most improve the lives of infertile couples? Clearly, access to care is limited and should be improved. However, infertility is rarely seen as a disease. By creating barriers to access, we trivialize both the medical and psychologic aspects of infertility. To those involved in caring for infertile couples, this callousness is mind-boggling, but it may be a paradoxical reaction (denial) elicited by the incredible importance that we attach as a society to reproduction. Again, many hold deep superstitions and may prohibit what is often seen as tampering with Mother Nature or playing God. In addition to limiting access to infertility care, another consequence of these attitudes is a lack of research about the causes of and best therapies for infertility. We clearly need more research on the mechanisms of embryogenesis, but this type of research is often viewed with the same suspicion as stem cell research. Research on implantation evokes the controversies of abortion politics. Clinical trials, which are sorely needed even if they do not specifically illuminate pathogenesis, would be especially useful for comparing the efficacies of current therapies so as to permit cost-benefit analyses; however, given the low probability of pregnancy in any given treatment cycle and the corresponding need for enrolling many subjects, such trials are often deemed as too expensive or not feasible in the short time frame demanded by federal and private funding agencies.

In short, infertility remains an area that is filled with taboos, superstition, mysticism, and awe. Herein we attempt to dispose of some of this baggage by considering the therapeutic implications of what is known about the causes of common infertility conditions.