Unexplained Infertility: What You Need to Know

Ask an Expert addresses reader questions. Today Dr. Bruce Lessey of Wake Forest University, will answer some questions related to unexplained infertility. Dr. Lessey is an internationally recognized leader in uterine receptivity research and the identification of markers associated with unexplained infertility. 

Disclaimer: This article is sponsored by ReceptivaDx

What should someone research if diagnosed with unexplained infertility? 

The concept of being “diagnosed” with unexplained infertility suggests it is medical condition. In actuality it is a diagnosis of elimination, meaning you are being ruled out of conditions known to cause infertility. For those women who still can’t get pregnant, it simply means the answer has not been found yet. The reason tests like ERA and ReceptivaDx have spread across the IVF landscape (and slowly into the OB community) is that they are another avenue to find the problem. If almost 50% of IVF centers still have women who don’t conceive or miscarry after running screening tests, it is not good enough to simply label these women with UI. There are options and looking at the dysfunction of the uterine lining is one. 

Is there an age group that’s affected by unexplained infertility the most?  

We assume that the older a patient gets; the more acquired defects may occur. Staying on endometriosis as the cause, teenagers with endometriosis may not be infertile but left to time, endometriosis may get worse, and they can become infertile. That’s why we see a lot of patients have unexplained recurrent loss first and then they progress to unexplained infertility because they were more fertile earlier in life and now, they’re less fertile.  

Is secondary unexplained infertility more common?  

Secondary infertility is less common.  It often relates to undiagnosed endometriosis that was existent before they got pregnant the first time and that was masked by them being on birth control pills. Other causes include acquired defects like adenomyosis which can happen by being pregnant or things that happen in pregnancy that can damage the uterus. 

When do you recommend getting a second opinion?  

Any patient that’s been through a workup and has unexplained infertility and her doctor doesn’t have a good plan should get a second opinion because otherwise they’re just paying the doctor and not getting anything for their money. Patients need to be proactive in this regard and be able to know that there are hidden reasons for infertility that can now be diagnosed using endometrial receptivity testing like we have with BCL6. I think in the future this will become standard of care especially for unexplained infertility. But right now, it’s left up to the patient to discover these things for herself. It’s important for the patient to advocate for herself and in some cases, educate her doctor if necessary. Centers testing for BCL6 are finding that treatment really does work, and their outcomes are improved even when they may still be non-believers of endometriosis as the cause. 

Idiopathic recurrent implantation failure - how close is science to figuring out why? 

There is idiopathic implantation failure in the setting of IVF and there’s also recurrent pregnancy loss. 

If you’re not getting pregnant and you’re putting back euploid (normal) embryos time after time, that’s recurrent implantation failure. Once you get pregnant, if you keep losing those pregnancies that’s recurrent pregnancy loss. Interestingly those two are tightly related and probably represent the same phenomenon on a spectrum. So, the patients who have recurrent implantation failure are a worst-case scenario than the patients who have recurrent pregnancy loss but they’re all the same in terms of their disease. They all have endometriosis in my opinion.  A paper just published in human reproduction shows about 80% in each group have undiagnosed endometriosis. Below is an excerpt for patients 

 WHAT DOES THIS MEAN FOR PATIENTS? 

Women who have multiple miscarriages may have something in common with those who are unable to conceive but have no abnormalities on routine testing. A protein called BCL6 has been found in samples from the lining of the womb (the endometrium) from women with endometriosis (a painful condition in which this tissue grows outside the uterus) as well as from women who are infertile but in whom all the common fertility tests are normal. 

We compared levels of BCL6 in samples of endometrium from women with repeated miscarriage, those whose infertility is unexplained and fertile women: we found that BCL6 levels were higher in the infertile and pregnancy loss groups. 

We feel the same pathway may be contributing to recurrent pregnancy loss as well as UI. Women with unexplained pregnancy loss have few treatment options at present, but this research may open new avenues for both treatment and future investigation into the mechanisms involved in unexplained pregnancy loss. 

What does 'borderline PCOS mean for my unexplained infertility?  

Women with polycystic ovarian syndrome clearly have an element of endometrial receptivity defects. So, anything that goes along with PCOS one should also think about whether there’s an implantation problem. It’s unclear whether this means that PCOS women also have endometriosis or whether the high androgen levels associated with PCOS may be affecting the endometrium. I think those are studies that clearly need to be done. But in the meantime, anyone with PCOS who doesn’t get pregnant fairly quickly with medications like Clomid should undergo testing to see if they also have an endometrial receptivity defect.  

How many cases of unexplained infertility are actually caused by endometriosis?  

If you read the literature, it suggests that up to 60% of unexplained infertility is related to endometriosis. We think it’s higher. Now that we have a sensitive endometrial biopsy test in BCL6 as well as additional biomarkers that are being studied and optimized, we think the percentage of undiagnosed endometriosis patients will get closer to 80% for unexplained infertility patients. 

Dr. Bruce Lessey of Wake Forest University. Dr. Lessey is an internationally recognized leader in uterine receptivity research and the identification of markers associated with unexplained infertility. He is the founder of the research on BCL6, the test you can order as ReceptivaDx. He has served on multiple editorial boards for major journals and published over 150 peer reviewed articles, with a focus on infertility, endometriosis and the role of the endometrium in embryo implantation. Just as important, Dr. Lessey still sees patients regularly at his Wake Forest location. He has more than 30 years' experience in IVF.  

Medical Disclaimer:

The information provided in this blog is intended for general informational purposes only and should not be considered as a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your healthcare provider or qualified medical professional with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this blog.