Progesterone Resistance – everything to know in 2025

Never heard of progesterone resistance? You’re not alone – but it could be a hidden factor standing in the way of a successful pregnancy. Did you know that: 

• one-third of women with endometriosis treated with progestins may not see results, due to progesterone resistance, according to the National Institutes of Health (NIH).
• and, it’s estimated that up to 30% of women with Polycystic Ovary Syndrome (PCOS) may not respond to progesterone-based therapies, according to the NIH. 

For women experiencing unexplained infertility, failed IVF cycles, or recurring pregnancy loss, progesterone resistance is a factor worth understanding. As reproductive science advances, more of us are learning about the real impact of this often-overlooked condition.

Here’s everything you need to know in 2025, with testing go-to ReceptivaDx™ providing the intel.

What is progesterone resistance?

Progesterone resistance is a condition in which the body’s cells – especially those in the uterus – don’t respond properly to the hormone progesterone. Progesterone is essential for preparing the uterine lining for embryo implantation, and for maintaining a pregnancy, but resistance can block these processes.

Why progesterone matters

After ovulation, rising progesterone levels thicken the uterine lining in anticipation of a fertilized egg. If implantation happens, progesterone keeps the lining intact and suppresses contractions to support a growing pregnancy. If resistance is present, that hormonal support system breaks down, making it harder for an embryo to implant or stay implanted.

What are the symptoms of progesterone resistance?

This is where things get tricky. Progesterone resistance symptoms often overlap with other reproductive health issues – or may be brushed off entirely as “just how your cycle is.”

Common signs include:

• Irregular periods or spotting
  
• Painful periods (dysmenorrhea)
  
• Heavy menstrual bleeding
  
• Infertility or recurrent miscarriage
  
• Failed IVF (despite good embryo quality)
  
• Premenstrual symptoms that are more intense or prolonged

Digging deeper

These symptoms are often associated with hormonal imbalance or endometriosis – but progesterone resistance might be the underlying cause. If your uterine lining isn’t responding to progesterone, the endometrium may not develop in a way that supports implantation, even during IVF. This resistance can also cause hormonal “miscommunication,” throwing off ovulation timing or embryo transfer success.

What causes progesterone resistance?

There’s no one-size-fits-all answer, but research pinpoints several root causes and contributing factors.

Leading causes include:

• Endometriosis: The number one associated condition, often hidden or undiagnosed
  
• Chronic inflammation of the endometrium
  
• Elevated BCL6 protein levels (a biomarker of inflammation that is genetically linked to progesterone resistance – read up for more info)
  
• Hormonal imbalances (especially estrogen dominance)
  
• Exposure to endocrine-disrupting chemicals (EDCs) in the environment
  

Endometriosis link

Endometrial tissue growing outside the uterus can interfere with normal progesterone signaling, making the endometrium less receptive. Studies show that up to 60% of women with unexplained infertility and a failed IVF cycle test positive for progesterone resistance or endometriosis-related inflammation.

How does progesterone resistance affect IVF?

This is where it gets especially relevant for anyone on a fertility journey.

Here’s how it plays out:

• During IVF, a high-quality embryo is transferred into the uterus.
  
• If progesterone resistance is present, the uterine lining may be too thin, too inflamed, or thickening may be poorly timed – making implantation less likely.
  
• Even if implantation occurs, the uterus may not be able to sustain the pregnancy, increasing the risk of early miscarriage.

Why that matters:

Standard IVF protocols assume the endometrium will respond to progesterone as expected. But in resistant cases, this assumption fails. 

Testing for progesterone resistance before or between cycles can dynamically change the outcome – offering a chance to tailor treatment to your body’s specific needs.

How to test for progesterone resistance

The current gold standard for testing is the ReceptivaDx™ test. It checks for elevated BCL6, a protein linked to both progesterone resistance and endometriosis-related inflammation.

What to know about BCL6 testing:

• It involves a small endometrial biopsy, typically performed in your health provider’s office
  
• The sample is sent to the lab, and results return in 5-6 days
  
• High BCL6 can indicate likely progesterone resistance or inflammatory conditions affecting implantation.

Who it’s for:

Anyone with:

• Unexplained infertility
  
• One or more failed IVF cycles
  
• Recurring early pregnancy loss
  
• Signs of endometriosis, with or without an official diagnosis
  

Next steps:

If you test positive, your fertility specialist can pivot your treatment. This may include anti-inflammatory protocols, laparoscopic surgery to address endometriosis, or modified hormone support to increase progesterone responsiveness.

How to treat progesterone resistance

There’s no magic bullet – but treatment can be highly effective when progesterone resistance is diagnosed correctly.

Common treatment approaches include:

• Hormone therapy (e.g., letrozole or depot Lupron to suppress estrogen and reduce inflammation)
  
• Surgical treatment for endometriosis (via laparoscopy)
  
• High-dose progesterone support during fertility treatment
  
• Anti-inflammatory medications or dietary interventions
  
• Targeted IVF protocols, often with adjusted timing and medications
  

Real-world example:

Someone with multiple failed IVF cycles might switch to a modified cycle after a positive BCL6 result – and achieve implantation. This is the kind of strategic shift ReceptivaDx makes possible.

Progesterone resistance and endometriosis

These two conditions are often two sides of the same coin.

Here’s why:

• Endometriosis can cause chronic inflammation and disrupt hormone signaling.
  
• This inflammation and disrupted signaling can lead to progesterone resistance.
  
• Even mild or “silent” endometriosis (without symptoms) can affect implantation.
  

Takeaway:

You don’t need a confirmed endometriosis diagnosis to have inflammation-driven fertility issues. A positive ReceptivaDx result can pick up on silent endometriosis and progesterone resistance, giving you a clearer path forward.

Why is this important in 2025?

We are navigating fertility in a very different landscape than our mothers did. We’re having babies later, using more assisted reproductive technology, and facing known but often invisible hurdles like autoimmune issues, hormone disruption, and chronic inflammation.

Key takeaways for millennials, Gen Z and beyond:

• Knowledge is power. Understanding your endometrium’s receptivity can avoid wasted time and financial resources.
  
• Early testing = smarter planning. Especially if you’re over 35 or pursuing egg freezing or IVF.
• You’re not alone. Reproductive health is complex, and conditions like progesterone resistance are finally getting the spotlight they deserve.

What to do next

If you’ve been struggling to conceive, or feel like IVF isn’t working even with good embryos, consider discussing progesterone resistance with your fertility specialist.

Start here:

• Book a consultation with your doctor or reach out to ReceptivaDx
• Learn about the ReceptivaDx BCL6 test 
• Read up on fertility and progesterone resistance, and how it can affect IVF success
  

At-a-glance – quickfire facts

Add these to your notes and shoot questions to your doctor for next steps and testing support.

1. Progesterone resistance means the uterine lining doesn’t respond properly to progesterone.
   
2. It can cause IVF failure, infertility, or recurrent miscarriage – even if your embryos are healthy.
   
3. It’s often linked to endometriosis, diagnosed or not.
   
4. The ReceptivaDx test screens for BCL6, an inflammation marker tied to progesterone resistance.
   
5. Treatment may include hormone suppression, surgical removal of endometriosis, or tailored IVF protocols.
   

In 2025 and beyond, awareness is everything. With smart testing, customized treatment, and the right support, progesterone resistance doesn’t have to stand in the way of your fertility story.