Is PMDD in your genes?

By Emily Atherton, guest contributor in collaboration with Lily Winter, Community & Events Manager at Samphire Neuroscience and PMDD advocate.

If you’ve watched your mum or sister struggle with PMDD and thought ‘this feels familiar’, it might not be a coincidence.

Premenstrual dysphoric disorder (PMDD) is estimated to be between 30-80% heritable (Cary, 2024). In other words, your genes play a part in why your luteal phase is a struggle every month.

Is there a PMDD gene?

The short answer? Not exactly. But let’s dig a little deeper.

Before we talk about genes linked to PMDD, there are a few things worth keeping in mind:

• Most genetic mutations are risk factors, not causes: Think of it like a running race- in the same way someone who starts 20m ahead is more likely to win the race, someone with a gene mutation is more likely to develop a disorder. It’s not a guarantee that person will win the race, or that that person will develop a disorder, but it contributes to the likelihood.
• Genetics is complicated: it’s not always as clear cut as you pulling the PMDD short straw from your parent’s gene pool.
• We’re still learning: Research is still ongoing and there’s a lot more work to do.

That said, let’s introduce you to the first gene that was linked to PMDD - ESR1. ESR1 encodes a type of estrogen receptor called ERα. Researchers thought that mutations in this gene could affect your arousal, serotonin system function, and estrogen sensitivity (Hao, 2007), which contributes to PMDD.

This doesn’t mean that ESR1 is the cause of PMDD. But it does suggest your estrogen sensitivity, the crux of PMDD, may be shaped by your genes. A few key genes aside from ESR1 support this idea.

Get Lutea™
Explore Nettle™

Genes as a risk factor for PMDD

If you’ve been following along with our blogs, you’ll know that PMDD is caused by an abnormal response to normal hormonal levels. And this response can be genetically driven.

1. ESC/E(Z) complex 

Research has found that women with PMDD express the genes for something called the estrogen-sensitive complex - ESC/E(Z) for short - differently than women without PMDD (Dubey, 2017). This protein complex has an important role in regulating how cells respond to estrogen. It’s what's known as an epigenetic regulator, which is a complicated way of saying the ESC/E(Z) complex silences genes when it interacts with estrogen - this is very important for controlling how your cells behave.

So, if this complex is dysfunctional, it means your body doesn’t respond properly to estrogen, leading to symptoms of PMDD.

2. GABAA receptors

The GABAA receptor is really important in calming down your brain but in PMDD, changed gene expression makes this function less effective. This is because you have a lower expression of its δ subunit - the part that responds to allopregnanolone (ALLO) (Stiernman, 2025).

ALLO is a neuroactive steroid that has a calming effect on your brain, so losing your δ subunit makes you less responsive to ALLO, meaning you’re more likely to experience anxiety, irritability, and emotional sensitivity during your luteal phase.

How does this affect your brain?

So now you know what these abnormal responses to hormones actually look like, we can focus on the part of the brain it affects, and how this leads to you experiencing emotional symptoms in your luteal phase.

The GABAA receptors we just explored are found in a part of your brain called the amygdala - your fear and emotion centre. Researchers found that if you have a lower expression of GABAAs’ δ subunit, your amygdala is over-active - especially in your luteal phase. This means your brain interprets things to be particularly anxiety inducing (Stiernman, 2025).

Why PMDD is not entirely genetic

You might now be wondering if both your abnormal reaction to hormones and resulting symptoms are linked to changes in your gene expression, why PMDD isn’t caused by your genes.

This is where your environment comes in. A genetic mutation doesn’t cause your PMDD, but instead acts to lower your resilience to future PMDD triggers. For example, you might have an abnormal ESC/(Z) expression which predisposes you to be more vulnerable to the effects of childhood trauma (explored in our blog ‘How childhood trauma shapes the PMDD brain’). It’s essentially a double-hit scenario.

In fact, your environment, such as a traumatic early life, doesn’t just act as a separate risk factor. It can also directly interact with your genes to shape their expression. This phenomenon is known as ‘epigenetics’ which is essentially how your genes can be switched on and off by environmental factors.

In summary, a genetic mutation alone isn’t enough to cause your PMDD, but add in some environmental triggers and you’ve got the perfect recipe.

The importance of research

Exploring the genetics of PMDD is an extremely important part in helping us find out what PMDD actually is, and how to treat it. For example, exciting new research found ‘epigenetic biomarkers’ (biological flags of genetic mutations) of postpartum depression can actually be used to predict PMDD in women (Kaminsky, 2025). This perfectly encapsulates the power of scientific research, and there’s plenty more to learn - specifically when it comes to your brain.

As you’ve read throughout this blog, your unique genetic profile shaped by your life experiences, can influence how your brain responds to hormonal changes. That's why a brain centered approach is so important. This is where Samphire comes in.

By taking a brain-centred approach to researching your menstrual cycle, we developed Nettle™ - a medical-grade brain stimulation device designed to help you manage your pain and regulate emotions during your luteal phase. Nettle™ is proof of how research can lead to innovative therapies that directly improve your PMDD experience.

The more we understand your biology, and your brain, the closer we get to PMDD care that works for you, breaking the cycle of what you might have expected your PMDD experience to look like. have feared was simply ‘written in your genes’.