Unexplained infertility (UI) is one of the most frequent infertility diagnoses given to women, encompassing up to approximately 30% of all cases. At CHR, we are not convinced that such a diagnosis actually exists; we believe that this is a misleading faux diagnosis that actually impedes patients from receiving appropriate infertility treatments.
A couple is given the diagnosis of unexplained infertility when they suffer from infertility, and undergo a diagnostic workup that fail to reveal a credible underlying cause for their condition. In other words, the diagnosis of UI is reached by default; it is a negative diagnosis, suggesting that a clinical problem exists somewhere but the likely cause for this problem has remained elusive.
When patients come to us with a presumptive diagnosis of unexplained infertility (UI), we very carefully evaluate them for the following four conditions: 1) endometriosis, 2) tubal disease, 3) POA, and 4) immunological infertility. In our experience, we will find evidence for one or more of these conditions in an overwhelming majority of cases.
Endometriosis is one of the great mimics in medicine. It may be present to a very mild degree and cause considerable symptoms, or affect a patient very severely without her even being aware that she has the condition. Diagnosis is further hampered by the fact that it is often microscopic in nature which means that, even during laparoscopy, by far the most reliable diagnostic technique available, the condition can be overlooked and/or underestimated in severity.
Whether so-called "mild endometriosis" causes infertility has remained under dispute. We very strongly believe that it does, and even more importantly, that it affects fertility adversely in many different ways. The strongest support for this position comes from research data on IVF cycles. Women with endometriosis have been reported to have fewer positive outcomes than other women of the same age without the disease.
These poor results are seen in practically all the aspects of the process. Patients with endometriosis typically have fewer eggs at time of retrieval, lower egg quality, and lower implantation and pregnancy rates. Additional investigations suggest a couple of possible mechanisms of how endometriosis affects fertility:
There are also many studies in the literature which point towards similar patient profiles between women with endometriosis and unexplained infertility. Putting all this together, we are convinced that at least some women, mistakenly labeled with “unexplained infertility,” in reality suffer from endometriosis-related infertility.
The high rate of misdiagnoses in tubal disease has been well documented in the medical literature. Most of these misdiagnoses can be attributed to the limitations of hysterosalpingography (HSG) the main screening technique utilized worldwide in the diagnosis of tubal disease. Indeed, CHR has been at the forefront of research on the reliability of HSG and quite convincingly demonstrated a number of years ago the limitations of the technique, as it is utilized in most radiology suites. At CHR we perform HSGs in a more sophisticated and more reliable way, called a Gyneco-Radiologic Study, or GRS, paying close attention to the tubal function in addition to the tubal anatomy.
As also reported by others, HSG is particularly poor in diagnosing correctly distal tubal disease (also called fimbrial tubal disease, tubal problems at the farthest from the uterus) and peritubal adhesions. In addition, the literature suggests that the reliable interpretation of HSGs suffers from considerable variability of interpretation. This was also confirmed by a study at CHR in which we reviewed outside HSG films and compared our reading to the original reading of the films by the radiologist. In over 100 reviews of these HSGs we disagreed significantly with the diagnostic reports that accompanied the original films in 60% of cases, suggesting that tubal issues are often overlooked by radiology reports.
HSGs have the ability to investigate only the anatomic condition of the fallopian tubes. While obviously these are important, the functionality of the oviducts, which cannot be evaluated by a HSG, is just as important. Oviducts can be assessed by measuring the tubal perfusion pressure (TPP) of the fallopian tube. When competent HSG is performed in combination with a TPP evaluation, this modified form of HSG is called a GRS. In over 80% of cases, high TPPs are associated with the laparoscopically confirmed presence of endometriosis, once again confirming not only that tubal disease is greatly under-diagnosed but that endometriosis is as well.
Therefore, little doubt is left that at least some cases of unexplained infertility represent the failure of proper diagnosis of tubal disease, especially distal and functional tubal disease, frequently associated with endometriosis.
It is now widely believed that ovaries age in a very specific pattern, along a typical aging curve which, in turn, is defined by the number of remaining follicles within the ovaries.
Women are born with approximately 300,000 follicles and that number declines by approximately half every 10 years. In parallel to this modest decline in follicular numbers, female fertility declines only modestly until approximately age 37.5 years, when roughly 25,000 follicles are left over. From that point on, the decline in fertility accelerates in parallel with accelerated follicular loss until menopause sets in at the average age of 51. It is now assumed that the period between acceleration in fertility decline (age 37.5 and 25,000 follicles) and menopause (age 51 and 1,000 follicles) is fixed at approximately 13.5 years.
Women with POA follow a similar curve; however their ovarian aging curve is, for reasons which are still unclear, moved to the left of the chart. In other words, they reach all the key points on the aging curve at much younger age, though at equal time intervals. This, of course, means that these women will not only face a dramatic decline in their fertility potential prematurely but will also enter menopause early. Indeed, the literature suggests that approximately 11% of women encounter menopause early. Many from amongst this very large pool of women can, therefore, also be expected to experience an accelerated fertility decline much earlier than the usual age of 37.5 years and, since they usually do not exhibit any specific symptoms, they are frequently diagnosed with unexplained infertility.
We believe that in infertility practices, where women with POA can be expected to be concentrated, they represent a surprisingly large percentage of patients. At CHR, we routinely find evidence of POA in a majority of our patients under age 38.
A timely and correct diagnosis in these women is of crucial importance. If they are correctly diagnosed with POA and if their infertility treatment is then geared towards their ovarian, rather than chronological, age, pregnancy rates with IVF will still be surprisingly excellent, as we demonstrated in our pregnancy rates in this patient population which is associated with very poor prognosis.
Therefore, the literature quite convincingly suggests that a considerable number of women with the presumed diagnosis of unexplained infertility actually suffer from POA.
Whether abnormal immune function can affect female fertility has remained a highly contentious subject. Many much esteemed colleagues vehemently argue that there is no evidence for such a connection. At CHR, we strongly disagree with them, even though we have to acknowledge that, so far, no treatment for immunological infertility has proven its value in properly conducted clinical trials.
The fact that we do not have a good treatment for immunological infertility, however, does not mean that it does not exist or does not require proper diagnosis. Indeed, we believe that the autoimmune literature provides overwhelming evidence in support of the fact that (auto)immune mechanisms can reduce female fertility potential. The most poignant one lies in the observation that women with classical autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma and others, long before they become clinically symptomatic and are diagnosed with their diseases, already demonstrate a significant decline in fertility. This has, by now, been demonstrated in a large number of studies all over the world, including one conducted at CHR.
We are therefore convinced that immune abnormalities, especially autoimmune factors, can adversely affect female fertility and need to be recognized as such. We see a very high prevalence of previously diagnosed and undiagnosed abnormal autoimmunity in our patients, and believe that at least some of the patients labeled with “unexplained infertility” actually suffer from immunological infertility. If left untreated, these abnormalities increase the risk of miscarriage once the patient conceives with treatment. Fortunately, in contrast to immunological infertility, immunological pregnancy loss can be successfully treated in many cases.
There may be several reasons why the fuzzy diagnosis of unexplained infertility is so widely given. One possibility is that there is no obvious cause for a couple's infertility and that their problem may be the result of multiple minor aberrations in how their respective reproductive systems cooperate. After all, the successful establishment of pregnancy is a highly complex process, and at least on a theoretical level, one can assume circumstances where male and female fertility are each affected only to such a mild degree that standard diagnostic test results would still be considered within normal range. Yet, together, the reduction in the couple's combined fertility potential may be large enough to cause infertility.
Whether such a circumstance indeed exists is highly questionable, however. Moreover, even if it did exist, it would be incumbent upon us to improve the sensitivity of our diagnostic testing, so that testing procedures will be able to detect even subtle and multifactorial abnormalities in the reproductive processes which can lead to infertility. Any such improvement in diagnostic abilities would then eliminate the need for a diagnosis of unexplained infertility, which brings us to the main rationale of our argument against the continuous use of this terminology: Since the diagnosis of unexplained infertility is a diagnosis of exclusion, it will be only as good (or bad) as the diagnostic workup that has been performed.
Another way of saying this is that the more comprehensively and the more accurately the diagnostic workup is performed, the more likely will a true cause for a couple's infertility be detected and the less likely will they end up with a diagnosis of unexplained infertility. The opposite is also true: the shoddier a diagnostic evaluation, the more likely will it end up with a diagnosis of unexplained infertility.
This, of course, creates a rather peculiar incentive structure: the poorer the medical care, the more likely a couple will end up with a diagnosis of unexplained infertility: exactly the opposite of what one would like to see with good medical practice in which good care should be rewarded by better diagnostic accuracy.
Physicians and their professional organizations disagree on what constitutes a complete infertility evaluation. The hypothetical conclusion that a couple suffers from unexplained infertility will, therefore, greatly vary between practitioners, and what is considered unexplained infertility in one practice may have a very specific diagnosis in another. Indeed, at CHR we have become convinced that the four very specific conditions are frequently overlooked and misdiagnosed as unexplained infertility. We have reached this conclusion not only based on observations in our own patients but also from a careful analysis of the medical literature. And, while the brief summary here does not allow us to offer the necessary detail of our literature review, we encourage our readers, who are interested in more detail, to contact us and we will gladly provide you with a more detailed manuscript.
The first step in treating unexplained infertility is finding the right diagnosis. Whenever patients come to us or request a second opinion from us with such a diagnosis, we very carefully reevaluate their diagnostic work-ups, with special focus on the four medical conditions (endometriosis, tubal disease, premature ovarian aging and immunological infertility), which are frequently missed and lead to the misdiagnosis of unexplained infertility.
Following such a policy, the prevalence of cases at CHR where we cannot identify the real cause of a couple's infertility has become very small. Once exact causes are established, we can tailor the treatment to address the individual underlying causes, leading to much better treatment outcomes.
