Unexplained infertility – what next? 3 steps to move things forward

Words by Jessie Day

Unexplained infertility affects between 10 and 30 per cent of couples trying to conceive, according to 2022 data. It’s a big number, but testing varies between healthcare providers, and what might be considered ‘standard’ testing by your doctor may be out of the ordinary for another clinic or team. 

This lack of a joined-up approach can be extremely frustrating, especially if diagnosis has been a challenge so far. But what is unexplained infertility, exactly? And once you have the diagnosis, what are the next steps? Kicking off 2023, we’re looking at possible causes – including new data around ‘silent endometriosis’ and a groundbreaking test called ReceptivaDx™ , which uses a protein marker known as BCL6 to identify women with uterine lining inflammation, most often associated with endometriosis.  We’ll also cover how to navigate next steps with your team. 

Have you tested for BCL6?  75 per cent of women with unexplained infertility will test positive for BCL6, a marker for inflammatory conditions – including silent endometriosis – the most common cause of unexplained infertility. Scheduling  a test using ReceptivaDx™  may provide much-needed clues to get to the root of your diagnosis. 

What is unexplained infertility? 

Unexplained infertility usually means that no cause, or ‘reason’, has been identified for your difficulties conceiving. For most people – or couples – diagnosed with unexplained infertility, standard fertility work-up tests will have ruled out: 

• uterine abnormalities
• ovulation issues 
• semen abnormalities 
• fallopian tube obstructions 
• diminished ovarian reserve (low egg count)
• hormonal concerns 

In general, your doctor may diagnose unexplained infertility when you’ve been trying to conceive (TTC) for, and/or have had: 

• at least a year if you’re under age 35, or 
• six months if you’re aged 35 or older
• multiple miscarriages
• at least one failed IVF cycle

As with so many aspects of TTC, there are very few absolutes when working through unexplained infertility, and diagnosis doesn’t mean you won’t – or can’t – get pregnant.

I’ve been diagnosed with unexplained infertility – what should I do next?

You’ve run all the tests, followed up with your doctor and started discussing your unexplained infertility diagnosis. For many in the TTC community, this is where the road-blocks sit. 

In our recent Insta poll, just 5 per cent of over 1,000 respondents had heard of, or been tested for, BCL6. Knowledge is power – and one of our fundamentals here on the FHH team – so if you’re hitting a brick wall with your treatment or diagnosis, BCL6 testing could be pivotal.

Step 1 – Prepare for pregnancy (and check your micronutrient levels) 

Unexplained infertility is rarely the end of a family-building journey. And while your team are working on a treatment plan, it’s important to keep the mind-set that you’re going to get pregnant. Maintain your preconception lifestyle – from stocking up on a good prenatal supplement, to minimizing alcohol and getting lots of sleep. 

Vital nutrients for healthy pregnancy, including folate, are best packed-into your diet a few months before conception to have a dynamic effect, so check your supplement and tweak your groceries list to include folate-rich produce like asparagus, spinach and Brussels sprouts. 

Now is also a great time to cover off any deficiencies you may have, and supplement accordingly, or change your diet-focus. Ask your team or look into these key nutrients, as a baseline: 

• Folic acid 
• Vitamin B6 & B12
• Vitamin D 
• Key minerals, including calcium, iron, iodine, zinc, magnesium, selenium & copper 

Key research published in 2021 recommends serum testing for these micronutrients, in women having difficulty conceiving.

Step 2 – Get more tests (including your BCL6 status)

Whether it’s failed IVF, recurrent miscarriages or what feels like an endless struggle to conceive, unexplained infertility can show up in many ways. 

But new, groundbreaking testing – available through many healthcare providers and centers, or direct – increasingly shows that women with unexplained infertility will test positive for a key protein – BCL6. 75 per cent of us, in fact, according to clinical research at ReceptivaDx™, part of Cicero Diagnostics, Inc. 

In our Insta poll, 70 per cent of respondents said their doctor had not covered endometriosis as a possible cause of their unexplained fertility. It’s a worryingly high number, given that inflammatory conditions of the uterus – such as endometriosis, silent or otherwise – may  ultimately be at the root of so many cases. 

New options

Inflammatory conditions, including ‘silent’ endometriosis, are proven to account for a significant percentage of infertility cases. But until the last few years, testing has been limited. Unexplained infertility, inflammatory conditions – particularly endometriosis – and other ‘hard-to-diagnose’ conditions have gone untreated, with many patients left reliant on their own research to push for investigation. 

ReceptivaDx™ is the first-of-its-kind test to identify inflammatory conditions like silent endometriosis, without resorting to expensive (and invasive) surgical laparoscopy. Even if laparoscopy is part of your treatment plan, it isn’t usually advised unless you have ‘major’ physical symptoms.

What is the BCL6 IVF (and fertility) connection?

Endometriosis – the presence of additional uterine tissue outside of the uterus – is a leading cause of implantation failure, miscarriage and infertility. During diagnosis, high levels of a protein called B-cell CLL/lymphoma 6 (BCL6) are often associated with inflammation, usually endometriosis. By testing for the presence of BCL6, ReceptivaDx™ is able to detect inflammation of the uterine lining – such as endometriosis – which can limit an embryo’s ability to implant, or ‘stick’.

In our recent Insta poll, just 5 per cent of over 1,000 respondents had heard of, or been tested for, BCL6. Knowledge is power – and one of our fundamentals here on the FHH team – so if you’re hitting a brick wall with your treatment or diagnosis, BCL6 testing could be pivotal. 

Nearly a quarter of women with endometriosis have no symptoms. For this group, ‘silent’ endometriosis can be extremely difficult to diagnose – or even investigate – making non-invasive testing like the ReceptivaDx™ option a key tool for patients with unexplained infertility. 

By doing the test, you’re either confirming an inflammatory condition (with a positive result), or ruling it out, and moving on with your investigation and treatment plan. 

What are the treatment options if my BCL6 test comes back positive?

There are two standard treatment approaches.

The first is surgical laparoscopy which can be used to remove the endometriosis from your uterus. The second is taking hormone suppression medication – usually Depot Lupron – for 60 days.  These quiet the inflammatory impact of the endometriosis, allowing for a better chance of successful transfer (if undergoing IVF), or improving the probability of getting pregnant naturally.

Women treated for a positive BCL6 result see a 5-fold improvement in successfully getting pregnant.

Schedule a test or find a center offering ReceptivaDx™, or ask your healthcare provider for more details.

Step 3 – Regroup (and ask lots of questions) 

A diagnosis, in any form, can be hard to hear. As a team, we’ve been there, and we don’t take this process lightly. But sitting down or connecting with your doctor, only to be told that your TTC struggles are ‘unexplained’, can be far more difficult, and frustrating. 

‘Unexplained’ does not mean a closed door, however. Or, it shouldn’t. If unexplained infertility becomes part of the conversation with your doctor – and your treatment plan – it’s time to ask a few key questions. For us, these included:

• Given my/our age, what should we do next?
• Are there any nutritional deficiencies we should look into? 
• Could any underlying medical conditions be causing our fertility issues?
• Can we look into hormonal testing? 
• Should we check for silent endometriosis? 

With all of this covered, booked in and in-play, you could move on to asking: 

• What treatment options do you recommend, and in what order? 
• When can we start treatment?
• What are the success rates like (in general and in-clinic) for people in my situation? 

Most importantly, keep asking ‘what next?’ There is almost always another option to try – another test to look into, or route to take. So if you want to try something else, and see more options from your team, just ask. 

Keen to rule out endometriosis – and silent endometriosis – from your unexplained infertility? Connect with ReceptivaDx™ to book your test.

TRB readers can claim $75 off a ReceptivaDX test, use code TRB23 on your test request form.