Unexplained infertility was a term utilized relatively frequently in the past, prior to the ability of reproductive endocrinologists to characterize some of the more subtle reasons for infertility. A couple was considered to have unexplained infertility if the woman ovulated and had a normal post-coital test and Hysterosalpingogram, and the man a normal Semen Analysis. When Laparoscopy was popularized in the 1970s and 1980s for diagnostic purposes in these “unexplained” cases, many women were found to have minimal pelvic findings that unfortunately led to further surgeries or medical treatment, which may have been unnecessary, but gave a diagnosis other than “unexplained.” Ultimately, the laparoscopic findings often delayed appropriate treatment, and distracted from following a more fruitful pathway. To confuse issues further, couples that were clearly fertile could be shown to have infertility factors!!! In addition, couples who were unsuccessfully treated to correct a known factor, like Anovulation; or Endometriosis, were then told they had “unexplained infertility,” when in truth they had treatment failure and needed to consider a different approach. Until IVF became successful, it was a last ditch effort, instead of an earlier option as it is today.

We know now that infertility is a statistical definition in many cases, and no absolute reason may exist. However, over time, certain functions can change so that “normal” test and “abnormal” tests may coexist within the same time frame. If enough tests are done, everyone will have something wrong…but does it matter? If a couple is not conceiving on their own, treatment should be aimed at improving the chances that normal sperm and a normal egg will get together to provide the opportunity to produce a normal Embryo. This may be as simple as enhancing Ovulation with clomiphene or gonadotropins, or doing intrauterine inseminations. If so-called conventional treatment fails, where the sperm and egg have been given the best conditions for joining up within the woman’s reproductive system, Assisted Reproductive Technology provides the best means of success through bypassing all the areas where things may be going wrong. Also neglected in the label of unexplained infertility was the most important factor of all: Age! The age of the woman, primarily, but also of the man, will predict the likelihood of pregnancy both through natural conception as well as with all levels of fertility treatment.

We know that as a woman ages, she has fewer eggs left in her ovaries, and those eggs are more and more likely to be developmentally and genetically abnormal; this results in fewer conceptions, and more miscarriages due to chromosomal abnormalities. The man, who had been given a free pass on his age because of the lack of a comparable end to fertility as is true with menopause, is now recognized as having a declining sperm quality as he ages, as well as increased sporadic genetic mutations. In addition, as reproductive endocrinologists performed more and more IVF cases, they were able to correlate poor outcomes with abnormal female Hormone levels and poor ovarian reserve. This can be detected during conventional treatment cycles as well, which would not only explain the unexplained, but point to more aggressive therapy. It may not be clear until a couple goes through IVF, and egg and embryo quality are examined that the reason for prior failures becomes evident. With the newest uses of Preimplantation Genetic Diagnosis in IVF, the finding of high proportions of abnormal embryos may explain everything.

If there is a suspicion that a couple has been conceiving but having early pregnancy losses, the approach would be to document such losses and then follow the additional testing for recurrent miscarriage, which would include chromosomal testing of the couple as well as looking for factors in the woman that could result in pregnancy losses. There can also be subtle effects on conception as well as the ongoing pregnancy that have to do with lifestyle: extremes in weight, smoking, alcohol use, exercise, illicit drug use, and poor nutrition, all can result in suboptimal reproductive performance that may or may not be shown by standard testing.

In summary, the absence of obvious reasons for infertility points to using treatment as both diagnostic and therapeutic modalities. In the process of trying to achieve a pregnancy, many things come to light, which may create a more or less favorable prognosis. In the end, the use of IVF provides a way to overcome many of the obstacles at once, and provide the best chance of success.