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.
'Unexplained' infertility generally means that the physician failed to find its TRUE cause.
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:
- fallopian tubes of patients with endometriosis may function abnormally
- ovarian function may be adversely affected by endometriosis
- endometriosis may release toxic substances that 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 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.
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 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.
Read more about Unexplained Infertility
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.