Or is it environmental?
PMDD is a complex condition, and it’s not fully understood why someone can develop it. However, we can be quite certain that it’s due to a combination of different factors that can even differ between people.
One of these factors is genetics. Twin studies put the heritability of premenstrual symptoms at up to 56% (1). More than half of your likelihood of having PMDD may come down to your genes. But that still leaves a large share, up to 44%, unaccounted for by heritability alone, which means the environment, life events, and the way your genes are switched on and off across your life all have room to play a role.
Important note: Carrying these genes doesn't necessarily mean you'll develop PMDD. Instead, it can create an underlying vulnerability, which other environmental factors and biological factors can then combine to trigger. This is also why PMDD can be present from someone's very first period, or for others it may not develop until later in life, following major life events such as having a first child.
Which Specific Genes Have Shown up in Studies? Some Relate to Hormone Responsiveness
A research paper published in Molecular Psychiatry in 2017, has identified a new genetic target: a group of genes called the ESC/E(Z) complex. Here, researchers grew immortalised blood cells from those with PMDD and controls and exposed them to estrogen and progesterone (2).
Even though the cells were in a dish, outside of the body, the PMDD cells still responded differently to the hormones than the control cells did. This means there is an intrinsic difference in the cells of those with PMDD.
Here's where it gets interesting: the PMDD cells produced more of the genetic "instructions" (mRNA) for building the ESC/E(Z) complex, but ended up with less of the actual protein it makes. Normally, more instructions should mean more of the finished product, so this mismatch suggests something goes wrong between reading the instructions and acting on them in PMDD cells. The hormone response was also different: when exposed to progesterone, the control cells switched on several related genes, while the PMDD cells barely responded at all (2).
This particular gene complex matters because two of its components have known links to PMDD symptoms: one, called PHF1, is involved in the GABA system (a calming brain chemical evidenced to have disrupted effects among those with PMDD) (3), and another, called SIRT1, has been linked to depression-like behavior.
Some Genes Relate to Serotonin.
Several other studies have explored candidate gene options for PMDD. Two Estrogen Receptor genes (ESR1 and ESR2) have been studied in association with PMDD.
In a study of 91 women with PMDD, DNA was extracted from blood and researchers looked at 3 target genes more closely (2). They found that ESR1 showed four significantly different polymorphisms (tiny variations in the DNA code between people) in women with PMDD compared to controls (4).
This makes sense: ESR1 is the gene that regulates the alpha estrogen receptor, which is implicated in mood regulation, specifically through effects on serotonergic signalling. There is separate evidence showing that serotonin signalling differs in women with PMDD compared to controls, and that it links to worse depressive symptoms (5).
Another study explored a gene involved in building the serotonin receptor itself (7). Researchers studied 104 women and found that those carrying one specific version of this gene (called the “C allele carriers”) had a 2.5x higher risk of PMDD compared to those without it.
Interestingly, this is the opposite of what's usually seen in other mental health conditions. There, it's typically the other version of the gene (the "G allele") that raises risk - as it increases the number of a type of serotonin receptor that dials down how much serotonin signaling happens overall (6).
It's worth noting that neither of these findings has been successfully repeated in follow-up studies, so we can't yet say how reliable they are (1).
Nature or nurture?
This is a bit of a trick question. The one genetic mark that holds for PMDD currently is more epigenetic (meaning it doesn't change the underlying DNA sequence itself, but affects gene activity). The complex identified can decide when genes are turned on or off, and it is heavily influenced by extrinsic factors, like hormones, for example. So, yes, it is genetic, but not in the sense that it stays the same from when you are born. It could, in effect, be turned on and off throughout your life.
Regardless, we are still missing up to 44% of factors that are not genetic. Which is important, because it highlights that if your grandmother, mother or sister has PMDD, that doesn’t necessarily mean you will too - other factors, not just genetics, can contribute to the pathophysiology of PMDD.
One main contributor not linked to genetics appears to be early-life trauma, though it’s important to note that this is not the experience of everyone with PMDD. In a large study of 11,973 women, 90% of women with PMDD reported a history of childhood adversity, compared with 27% of women without PMDD (7). In a 2025 systematic review of 26 studies, those with PMDD were twice as likely to have experienced trauma, compared to those without PMDD. Around one in five with PMDD also met the criteria for post-traumatic stress disorder (PTSD) (8).
When the nervous system is exposed to threat or adversity in childhood, it’s not just something you’re “dealing with in your head”. It has real onward, and often lasting effects on our biological systems. Inflammation is upregulated in response, and when this happens while the brain is still developing (a “critical window”, it can alter molecular pathways in our brain - neurotransmitter systems, brain circuitry and HPA axis function. This can then continue to affect us later in life, as it has even been shown to rewire how the brain responds to hormones, which may be one way it contributes to PMDD symptoms. You can read our article on PMDD and trauma here.
The Takeaway
PMDD can be written into your cells themselves, and it sits at a middle ground between nature and nurture - it's epigenetic…according to today’s evidence at least. Different external factors can shape how your genes turn on and off, and how your body responds to the normal hormonal fluctuations every month. Genetic research into PMDD might not give us a straight answer of how heritable the condition is, but it brings us one step closer to knowing more about it, which can ultimately lead to more targeted care, and perhaps in time, prevention.
References
1. Hantsoo L, Payne JL. Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA. Neurosci Biobehav Rev. 2023 Jun;149:105168. doi: 10.1016/j.neubiorev.2023.105168. Epub 2023 Apr 12. PMID: 37059403; PMCID: PMC10176022.
2. Dubey, N., Hoffman, J., Schuebel, K. et al. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry 22, 1172–1184 (2017).
3. Stiernman L, Comasco E, Johansson M, Bixo M. Transcription of GABAA receptor subunits in circulating monocytes and association to emotional brain function in premenstrual dysphoric disorder. Transl Psychiatry. 2025
4. Huo L, Straub R, Roca C. Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene Biological Psychiatry, 2007; 62, 925-933.
5. Sacher J, Zsido RG, Barth C, Zientek F, Rullmann M, Luthardt J, Patt M, Becker GA, Rusjan P, Witte AV, Regenthal R, Koushik A, Kratzsch J, Decker B, Jogschies P, Villringer A, Hesse S, Sabri O. Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study. Biol Psychiatry. 2023 Jun 15;93(12):1081-1088.
6. Dhingra, V., Magnay, J., O'Brien, P., Chapman, G., Fryer, A., & Ismail, K. (2007). Serotonin Receptor 1A C(-1019)G Polymorphism Associated With Premenstrual Dysphoric Disorder. Obstetrics & Gynecology, 110(4), 788–792. https://doi.org/10.1097/01.AOG.0000284448.73490.ac
7. Yang Q, Thornorethardottir EB, Hauksdottir A et al (2022) Association between adverse childhood experiences and premenstrual disorders: a cross-sectional analysis of 11,973 women. BMC Med 20:60
8. Grewal, J.K., Mu, E., Li, Q. et al. The prevalence of traumatic exposure in women with premenstrual dysphoric disorder (PMDD): a systematic review. Arch Womens Ment Health 28, 723–740 (2025). https://doi.org/10.1007/s00737-024-01536-z
