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What causes PMS & PMDD?
Summary
PMS and PMDD affect millions of people, yet their causes remain complex and multi-layered. This article explores the leading scientific theories behind why some people experience these conditions more severely than others - from hormone sensitivity and neurotransmitter changes to genetic predisposition, inflammation, and immune system involvement.
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🌿 Key takeaways
What causes PMS and PMDD: what to know
- PMS and PMDD are not caused by abnormal hormone levels - people with these conditions have the same hormone concentrations as those without. The key difference is neurobiological sensitivity to normal hormonal change
- Allopregnanolone - a progesterone metabolite - activates GABA receptors that regulate anxiety, stress, and fear. People with PMS and PMDD appear to respond differently to allopregnanolone
- People with PMDD may have up to 18% more serotonin transporters, clearing serotonin from the brain faster in the luteal phase
- Genetics play a role: if a parent experiences PMS or PMDD, their daughter is more likely to as well. Specific gene variants linked to oestrogen receptor function have been identified
- Chronic stress may increase susceptibility to severe PMS and PMDD symptoms by up to 25 times - creating a feedback loop that lifestyle changes can help break
What are PMS and PMDD?
Premenstrual syndrome (PMS) is a common condition occurring in the second half of the menstrual cycle - the luteal phase, after ovulation and before a period. Around 75% of people who menstruate experience it. It involves physical, psychological, and behavioural changes.
Premenstrual dysphoric disorder (PMDD) is a severe form of PMS, classified as a type of depressive disorder. Around 3 to 8% of people who menstruate experience PMDD. It can significantly impact work, social life, and relationships - and in some cases can lead to suicidal thoughts.
⚠️ If you need support now: If you are experiencing suicidal thoughts as part of PMDD, please reach out. Samaritans are available 24/7 on 116 123 (free, UK). You can also text SHOUT to 85258. Call 999 or go to A&E if you are in immediate danger.
Diagnosing PMS and PMDD
A diagnosis is made by a healthcare professional after symptom diary review over two to three cycles, medical history assessment, and where necessary a physical examination and blood tests to rule out other causes. For PMS, symptoms must occur during the luteal phase, subside after the period, and be severe enough to affect daily life. For PMDD, five or more symptoms including at least one mood-related symptom must be present in the luteal phase, to a degree that disrupts daily functioning.
Causes of PMS and PMDD
The exact causes are not fully understood, but it is likely that multiple factors contribute:
- Individual sensitivity to hormones and their metabolites
- Hormonal fluctuations (oestrogen and progesterone) during the luteal phase
- Neurosteroid and neurotransmitter changes (allopregnanolone, GABA, serotonin, glutamate)
- Genetic factors
- Inflammation and immune system involvement
Individual sensitivity to hormones
Many sources point the finger at hormones - but it is more nuanced than that. Most people experience similar cyclical hormonal changes every 28 days or so. If PMS and PMDD were solely caused by hormonal fluctuations, everyone would experience them. They do not.
Studies have confirmed that people with PMS or PMDD have the same hormone concentrations in their blood as those without. The key difference is not the level of hormones - it is individual sensitivity. Scientists believe people with PMS and PMDD are more sensitive to hormones and their metabolites. The more sensitive someone is, the more severe their symptoms may be.
🧠 In simple terms: PMS and PMDD are not caused by having "too many" hormones. They are caused by the brain and nervous system responding unusually strongly to normal hormonal changes. This is why they are increasingly understood as neurobiological conditions - not purely hormonal ones. Some studies show that people with PMDD are more likely to experience mood symptoms at other times of hormonal change - after childbirth, or in perimenopause - further supporting the sensitivity theory.
Hormone fluctuations
Progesterone
Because progesterone is only produced in the luteal phase - and PMS and PMDD symptoms only occur in the luteal phase - progesterone is thought to play a central role. In the second half of the luteal phase, both progesterone and oestrogen drop rapidly. It is this fall that is thought to trigger symptoms in sensitive individuals.
Evidence supporting progesterone's role
- Studies show that during anovulatory cycles (no ovulation, no progesterone), PMS symptoms do not occur
- Some COCs that suppress ovulation and prevent progesterone from rising also prevent or reduce PMS and PMDD symptoms
- COCs containing drospirenone - a structurally different form of progestogen - are effective as first-line treatment for many people with PMS and PMDD
⚠️ Worth noting: Not everyone finds COCs helpful for PMS or PMDD. Some COCs contain a synthetic progesterone that certain people do not tolerate as well, which can worsen symptoms. It is not entirely clear whether these effects are due to progesterone itself, or its metabolite allopregnanolone.
Oestrogen
Oestrogen tends to make us feel good. It is high during the follicular phase and contributes to feelings of happiness and positivity. Its role in PMS is not so much that it causes problems directly - but that when it is low in the second half of the luteal phase, there is very little positive to counter the negative. The absence of oestrogen's uplifting effects amplifies the impact of other hormonal changes.
Neurosteroids and neurotransmitters
Allopregnanolone and GABA
When progesterone is broken down, one of the substances produced is allopregnanolone - a neurosteroid that binds to and activates GABA receptors in the brain. GABA receptors control emotions such as anxiety, stress, and fear, and affect digestion, immunity, mood, and energy regulation.
In high concentrations, allopregnanolone has an anti-anxiety and calming effect. In lower concentrations, it triggers negative mood and depression. During the second half of the luteal phase, both progesterone and allopregnanolone fall - and it is thought that this drop triggers PMS and PMDD symptoms in those who are sensitive to these changes.
Research shows that people with PMS or PMDD:
- React differently to GABA, suggesting their receptors have atypical sensitivity to GABA and allopregnanolone
- Have lower levels of GABA in their blood than those without PMS or PMDD
- Experience a decrease in GABA between the follicular and luteal phases - whereas people without PMDD experience an increase
- Experience a change in the configuration of GABA receptors during the luteal phase
🧪 Stress and GABA: There is evidence that continued exposure to stress may blunt the allopregnanolone-GABA response over time. People with high levels of chronic stress could be up to 25 times more likely to experience severe PMS and PMDD symptoms. Since PMS can cause stress, and stress can worsen PMS, this creates a negative feedback loop - which is one reason why stress reduction strategies can meaningfully reduce symptom severity. See lifestyle changes that can help.
Serotonin
Serotonin regulates mood, sleep, and anxiety - and it has been implicated in PMS and PMDD. Both progesterone and oestrogen influence serotonin levels. A 2023 study found that people with PMDD may have up to 18% more serotonin transporters in the brain during the luteal phase - meaning serotonin is cleared from the brain faster, reducing perceived wellbeing.
This helps explain why SSRIs (which block these transporters) are effective for PMDD - and why they often work remarkably quickly, sometimes within days, unlike in generalised depression where improvement may take weeks.
Glutamate
Some studies suggest that glutamate - a neurotransmitter that regulates mood - may also play a role. Most people experience fluctuating glutamate levels across the menstrual cycle, but research suggests that those with PMS or PMDD may have increased sensitivity to these changes, exacerbating mood-related symptoms. This has not yet been conclusively demonstrated in research and further study is needed.
Genetics
Evidence shows a link between PMS and PMDD across generations and between twins. If a parent experiences PMS or PMDD, their daughter is more likely to as well - suggesting certain genes may increase susceptibility.
Key findings
- A link between specific gene variants and PMS and PMDD was first identified in 2007, when researchers established an association with variants of the oestrogen receptor ESR1
- Studies since then have found multiple differences in gene expression between people with PMDD and those without
- The altered GABA receptor response seen in PMS and PMDD may be caused by genetic alterations or differences in gene copy number - though diet and lifestyle can influence which genes are expressed, providing important support for a holistic approach to symptom management
Immune system and inflammation
PMS and PMDD symptoms may be related to the immune system and inflammation. Inflammation is a normal and necessary bodily response, enabling us to respond to stressful conditions. However, long-term or chronic inflammation can harm physical and mental health.
Evidence supporting inflammatory involvement
- Inflammation naturally changes across the menstrual cycle. Emerging evidence indicates that people with PMS and PMDD have higher inflammatory markers in their blood than those without
- Studies have found that common PMS and PMDD symptoms - including low mood, cramps, appetite changes, and bloating - are associated with higher levels of chronic inflammatory markers
🧠 In simple terms: It is not yet clear whether PMS and PMDD contribute to inflammation, or inflammation contributes to PMS and PMDD. But the correlation is consistent and important - and one reason why anti-inflammatory nutrients like omega-3, curcumin, and EPO are relevant to PMS and PMDD management.
Related articles
- Can supplements really help PMDD? Here's what the science says
- Evelyn's guide to talking to your GP about PMS and PMDD
Disclaimer: This content is for informational purposes only and is not intended as medical advice. Always speak to a qualified healthcare professional about any health concerns.
