Unexplained Infertility
What is unexplained infertility? Does it really exist? How is it treated?
What is Unexplained infertility?
Unexplained infertility (UI) is the most frequent infertility diagnosis given to women, encompassing up to approximately 30% of all cases. However, at the CHR we are not convinced that such a diagnosis actually exists and, even if it did, we believe that unexplained infertility would represent a misnomer that should be changed.
Unexplained infertility generally means the physician failed to find the TRUE cause of your infertility
A couple that has been assigned the diagnosis of unexplained infertility (UI) obviously suffers from infertility and has undergone a diagnostic work up that failed 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 but that the probable cause for this problem has remained elusive.
Conditions misdiagnosed as unexplained infertility
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.
| Common conditions misdiagnosed as unexplained infertility: |
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1. Endometriosis
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 endometriosis often is only microscopic in nature which means that, even during laparoscopy, the by far most reliable diagnostic technique available, the condition can be overlooked and/or underestimated in severity.
Whether so-called "mild endometriosis" causes endometriosis 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 which suggests that women with endometriosis have fewer positive outcmoe than other women of the same age without the disease. .
These poor results are seen in practically all the aspects of the process, from having fewer eggs at time of retrieval, reduced quality of the eggs, and having lower implantation and pregnancy rates. Additional investigations, which have attempted to elucidate why that would be the case, suggest (as we will discuss below in more detail) that their fallopian tubes may function abnormally, that ovarian function may be adversely affected and that endometriosis may release toxic substances which may harm embryos and/or their implantation capacity.
There are also many studies in the literature which point towards similar patient profiles between women with endometriosis and UI. Putting all of this information together, we are, therefore, convinced that at least some women, erroneously labeled with a diagnosis of unexplained infertility, in reality suffer from endometriosis-related infertility.
2. Tubal disease
The high rate of misdiagnosis of tubal disease has been well documented in the medical literature. Most of this misdiagnoses can be attributed to the limitations of hysterosalpingography (HSG), the principal diagnostic screening technique utilized world-wide in the diagnosis of tubal disease. Indeed, CHR has been in 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, therefore, more reliable way, called a Gyneco-Radiologic Study, or GRS).
As also reported by others, HSG is particularly poor in diagnosing correctly distal (i.e. fimbrial) tubal disease and peritubal adhesions. In addition, the literature suggests that the reliable interpretation of HSGs suffers from considerable variability of interpretation. This is also confirmed by a currently ongoing study at CHR in which we review outside HSG films and compare ours to the original reading of the films by the radiologist. So far in over 100 reviews of these HSGs we have significantly disagreed in over 60% of cases with the diagnostic reports that accompany the original films.
HSGs have only the ability to investigate the anatomic condition of the fallopian tubes. While obviously these are important, the functionaility of the oviducts, which cannot be evaluated by a HSG, is equally 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 a HSG is called a GRS. In over 80% of cases elevated 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 UI represent the failure of proper diagnosis of tubal disease, especially distal and functional tubal disease, frequently associated with endometriosis.
3. Premature ovarian aging (POA)
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 one 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 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 often unclear, moved to the left of the chart. In other words, they reach all the key points on the aging curve, noted above, 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 before the usual age of 37.5 years and, since they usually do not exhibit any specific symptoms, they are frequently mistakenly diagnosed with unexplained infertility.
We believe that in infertility practices, where women with POA can be expected to be concentrated, they will represent a surprisingly large pool 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 because, if such women are correctly diagnosed with POA and if their infertility treatment is then geared towards their ovarian, rather than their chronological, age, pregnancy rates with IVF will still be surprisingly excellent, as we demonstrated in our pregnancy rates in this patient population with very poor prognosis..
Therefore, the literature quite convincingly suggests that quite a considerable number of women with the presumed diagnosis of unexplained infertility actually suffer from POA.
Contact Us to see if POA might be behind your unexplained infertility.
4. Immunological infertility
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 auto-immune 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 auto-immune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma and others, long before they become clinically symptomatic and, therefore, 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 a recent study conducted at CHR.
We, therefore, are convinced that immune abnormalities, especially autoimmune factors, can adversely affect female fertility and need to be recognized as such, if for no other reason because the same abnormalities, once the patient does conceive with treatment, increase the risk of miscarriage, if left untreated. In contrast to immunological infertility, immunological pregnancy loss can in many cases be successfully treated.
Following this argument, it also appears logical to assume that at least some cases, wrongly diagnosed as unexplained infertility, in reality suffer from immunological infertility.
Why do so many doctors misdiagnose unexplained infertility?
The reasons why underlying problems may not be identified can, of course, vary. One possibility is that there is no one 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, each, are affected only to such a mild degree that standard diagnostic test results would still be considered within normal parameters. Yet, together, the reduction in the couple's combined fertility potential is large enough to cause infertility.
Since the diagnosis of UI is a diagnosis of exclusion, it will be only as good (or bad) as the diagnostic work up that has been performed
Whether such a circumstance, indeed, exists is, however, highly questionable. Moreover, even if it did exist, it would behoove us to improve the sensitivity of our diagnostic testing, so that testing procedures become 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, of course, eliminate the need for a diagnosis called UI, which brings us to the main rationale of our argument against the continuous use of this terminology: Since the diagnosis of UI is a diagnosis of exclusion, it will be only as good (or bad) as the diagnostic work up that has been performed.
Another way of saying this is that the more comprehensively and the more accurately the diagnostic work up 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 UI. The opposite is also true: the shoddier a diagnostic evaluation, the more likely will it end up with a diagnosis of UI.
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 UI: 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 UI will, therefore, greatly vary between practitioners, and what is considered UI in one practice may have a very specific diagnosis in another. Indeed, at CHR we have become convinced that four very specific conditions are frequently overlooked and, therefore, misdiagnosed as UI. We have reached this conclusion not only based on observations in or own patient population but also from a careful analysis of the medical literature. And, while the brief summary, presented here, does not allow us to offer the necessary detail of our medical literature review (inclusive of references), we encourage our readers, who are interested in more detail, to contact us and we will gladly provide you with a more detailed manuscript.
Unexplained infertility treatment
The first step in treating unexplained infertility is finding the right diagnosis. Whenever patients are referred to us with such a diagnosis we very carefully reevaluate their diagnostic work-ups, with special concentration on the four medical conditions described above, which in our opinion, so often are missed, leading to the misdiagnosis of UI. Following such a policy, the prevalence of cases where we can not identify the presumptive cause of a couple's infertility has become very small. So, we invite you to contact us for a second opinion about your unexplained infertilty diagnosis by simply completing the unexplained infertility emaill consultation form.
Written by Norbert Gleicher, MD
Last Updated: February 22, 2013
