BY MARLEIGH SMITH, NEUROSCIENTIST AT DITTO
What do we mean by ‘hormone sensitivity’? What’s actually going on in your brain?
The neurobiology of premenstrual dysphoric disorder (PMDD) has been increasingly researched in recent years, and still, neuroscientists have yet to come to clear conclusions.
Findings range from:
• A dysfunction in neurotransmitter (brain chemical) systems
• Actual physical changes in your brain’s structure.
Well, who’s right? With different subtypes of PMDD emerging in recent years, the truth is that the mechanisms behind PMDD are likely to be different between people, and could combine in a multifactorial way.
What Brain Chemicals Could be Influencing your PMDD?
As we know, PMDD is not caused by abnormal hormone levels in your body, but rather the sensitivity to hormonal fluctuations that those with PMDD do not have.
This could be because of interactions between the hormones and certain brain chemicals (aka neurotransmitters).
- GABA, one of the main neurotransmitters in our brains, is often called the “calming chemical”, as it has inhibitory effects in your neural networks.
- Serotonin, also a main neurotransmitter, is known as the happy chemical.
Both systems involving GABA and serotonin are thought to be dysregulated in PMDD. Let’s dive in.
The “Calming” (aka GABAergic) System Doesn’t Work So Well
The GABAergic system includes the brain chemical called GABA, and GABA receptors, which are made up of many different subunits. These subunits are responsive to ALLO, a metabolite of progesterone, which produces a calming effect.
In fact, ALLO works similar to anxiety medication, allowing a normal GABAergic, or calming system to be present in the brain.
In the late luteal phase progesterone falls, leading to a decline in ALLO. Normally, during this phase, certain GABA receptor subunits (“delta”) are upregulated, to compensate for the loss of the calming effect that ALLO gives, and ensure that the calming effect is left unchanged.
However, in PMDD, this is not the case. Studies show that there is different GABA delta subunit expression across the menstrual cycle in women with PMDD, and this upregulation fails to happen, meaning there is reduced GABA activity in the late luteal phase as progesterone falls - and less of a balancing “calming” effect (4). This is what produces the mood changes seen in PMDD.
Indeed, a study found that this decreased delta subunit expression was linked to higher amygdala activation in the luteal phase (4). The amygdala is essential for processing emotions. Higher amygdala activation can lead to emotional volatility and hyper reactivity PMDD symptoms.
The Serotonin System and Depressive Symptoms
A recent study provided evidence for a heightened sensitivity in the serotonin system in PMDD. Researchers used PET brain imaging and found:
- PMM Patients: They had an 18% increase in midbrain serotonin binding
- Controls: They had a 10% decrease in midbrain serotonin binding
during the premenstrual phase.
This study looked at serotonin binding on the presynaptic receptor, which promotes serotonin reuptake and reduces the availability of serotonin to bind to postsynaptic receptors, the process that creates the ‘happy’ effect of this neurotransmitter. Those with PMDD experience depressive symptoms due to this serotonergic dysregulation.
PMDD as an Inflammatory Condition
More and more research is alluding to the fact that PMDD is an inflammatory condition.
PMDD sufferers often have elevated peripheral inflammatory markers, where higher levels of these inflammatory markers are associated with PMDD symptoms (6). This inflammation in the body can reach the brain, and interact with:
• The previously mentioned neurotransmitter systems (GABA and serotonin)
• Our stress response system (the Hypothalamic-Pituitary-Adrenal (HPA) axis).
The HPA axis is influenced by systemic inflammation, and is seen to have lower activation in PMDD patients, which leads to an impaired stress response system in those with PMDD. This inflammation causes dysregulation in the brain, again contributing to PMDD symptoms.
*Check out our article on PMDD and ADHD to learn about PMDD and trauma, which relates to neuroinflammation! Find it here.*
What Brain Structure Changes are Observed in PMDD?
Recent studies show that differences in white matter volume*, grey matter volume* in our brain, plus connectivity between brain regions can contribute to how PMDD manifests.
1. A Baseline Difference in Brain White Matter in PMDD
In a 2025 study, brain imaging (MRI) was completed in the mid-follicular phase (where PMDD symptoms are unlikely to be present) and the late luteal phase, where symptoms of PMDD are most common (1). They observed:
• PMDD Differences vs “Healthy Controls”: Increased white matter volumes in women with PMDD at BOTH phases of the menstrual cycle, and there were no significant differences between the two phases.
• Regions impacted: Those involved in cognitive and emotional processing, and emotional regulation (inferior fronto-occipital fasciculus and uncinate fasciculus fornix).
Since the white matter volume changes are not significantly different between the asymptomatic and symptomatic menstrual phases, it appears that there is always a baseline difference between those with PMDD and controls throughout the cycle, rather than a transient change during the late luteal phase.
2. Baseline and Cycle-Specific Differences in Brain Grey Matter in PMDD
In a 2024 study researchers found (2):
• Persistent Baseline Differences: Those with PMDD had thinner cortices, (the outer edges of the brain), and reduced brain folding vs controls, which did not change with menstrual cycle phase. Again, this shows that there are baseline differences between those with PMDD and controls, rather than transient changes during the late luteal phase.
• Dynamic Cycle-Specific Changes: However, specific brain structure changes were seen across the menstrual cycle. In the late luteal phase, cortical thickness decreased compared to the mid follicular phase. Complex folding changes also occurred throughout the cycle. This shows specific phase changes in PMDD in grey matter structure, which was not observed in white matter volume changes in those with PMDD.
*We have a whole article written on how PMDD can be seen on brain scans! Go check it out here.*
Brain Connectivity Changes in PMDD
Potential impact on concentration, overwhelm, motivation, interest, pain sensitivity
It’s not just brain structure changes, but also the activity within these brain structures that could influence PMDD. Women with PMDD have decreased connectivity in the default mode network, which is essential for emotional processing, irrespective of the menstrual cycle phase (3).
Additionally, decreased connectivity in the central executive network, essential for high level cognitive processes was observed in PMDD sufferers.
Interestingly, differences in the salience network were observed to be different across all phases in those with PMDD, which is responsible for responses to external information.
These state-like brain changes explain that PMDD sufferers have distinct baseline differences in their neurobiology compared to controls, and also shows how there are specific changes in the luteal phase, where PMDD sufferers experience symptoms, creating a combinatorial effect.
How are these Systems Interacting?
In summary, current research points to the neurobiology of PMDD being defined by:
1. Dysregulation in key brain chemical systems
2. Inflammation within the wider body and brain!
3. Actual changes in the structure of your brain and it’s connectivity
With dysregulation in neurotransmitter systems, like maladaptive GABA subunits and serotonergic unavailability, the resulting signals sent from one brain region to another are different in those with PMDD, which can affect functional connectivity. On top of this, differential white and grey matter can also affect how these systems connect, and how your brain regions communicate, creating dysregulation in your brain as a whole, which contributes to the debilitating symptoms of PMDD. Surrounding inflammation further exacerbates this.
These 3 concepts produce vulnerability in the brains of those with PMDD, and will contribute to the heightened sensitivity to hormonal changes during the menstrual cycle. During the follicular phase, hormones are stable, so these neurobiological changes aren’t noticeable to PMDD sufferers, but when progesterone fluctuates in the luteal phase, this is when symptoms appear.
What Does This Mean for the Future of PMDD Treatment?
Actually, the increasing amount of research in this area, though not giving definitive answers about the neurobiology of PMDD, brings us closer to finding answers about the sensitivity of those with PMDD during changes in hormones. In fact, defining PMDD subtypes by their neurobiology and biological hallmarks can help create more personalized solutions for PMDD sufferers.
The more research and understanding there is of the small scale biological mechanisms in PMDD, the more solutions can be made!
References:
1. Stenhammar E, Dubol M, Stiernman L, et al. White Matter Regional Volumes in Relation to Menstrual Cycle Phase and Premenstrual Dysphoric Disorder. Biological Psychiatry Global Open Science. 2025 Nov;5(6):100573. DOI: 10.1016/j.bpsgos.2025.100573. PMID: 41017818; PMCID: PMC12466263.
2. Dubol M, Stiernman L, Sundström-Poromaa I, Bixo M, Comasco E. Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder. Journal of Affective Disorders. 2024 Jun;355:470-477. DOI: 10.1016/j.jad.2024.03.130. PMID: 38552916.
3. Reuveni I, Dan R, Canetti L, et al. Aberrant Intrinsic Brain Network Functional Connectivity During a Face-Matching Task in Women Diagnosed With Premenstrual Dysphoric Disorder. Biological Psychiatry. 2023 Sep;94(6):492-500. DOI: 10.1016/j.biopsych.2023.04.001. PMID: 37031779.
4. Stiernman, L., Comasco, E., Johansson, M. et al. Transcription of GABAA receptor subunits in circulating monocytes and association to emotional brain function in premenstrual dysphoric disorder. Transl Psychiatry 15, 255 (2025). https://doi.org/10.1038/s41398-025-03465-6
5. Sacher J, Zsido RG, Barth C, et al. 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;93(12):1081-1088.
6. Cheng M, Jiang Z, Yang J, et al. The role of the neuroinflammation and stressors in premenstrual syndrome/premenstrual dysphoric disorder: a review. Frontiers in Endocrinology. 2025 ;16:1561848. DOI: 10.3389/fendo.2025.1561848. PMID: 40225329; PMCID: PMC11985436.