It's Not Just Hormones: Scientists Uncover a Brain Mechanism Behind PMDD

“Is it that time of the month yet?”

How many times have we heard that one? Emotional symptoms tied to menstruation are often dismissed as “just hormones”, minimizing their credibility and impact on women. However, researchers may have just found one of the key molecular mechanisms driving these behavior patterns in the brain. 

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder estimated to affect 115 million women worldwide. This chronic condition is characterized by depressed mood, increased anxiety and irritability, and heightened emotional reactivity during the luteal phase of the menstrual cycle. The luteal phase is the third stage of the four-phased monthly cycle, occurring between ovulation and menstruation, where progesterone levels rise before dropping sharply. This is more than just PMS — PMDD severely affects a woman’s work, relationships, and day-to-day living. Yet, despite these serious effects, PMDD remains a misunderstood and understudied clinical diagnosis in women’s health. 

So why do the brains of some women react differently to these monthly hormone fluctuations? A clinical sciences research team at Umeå University in Sweden may have just unlocked the answer. To understand their findings, it helps to think of the brain as a system that constantly balances excitation and inhibition, like a set of accelerators and brakes. GABA-A receptors are a key part of that braking system. When activated, they reduce neuronal excitability and promote the body to relax and destress. 

" (...) women with PMDD seem to experience the opposite. Instead of calming effects, ALLO seems to (...) intensify emotional responses."

During the luteal phase, the body produces a neurosteroid derived from progesterone, called allopregnanolone, or ALLO. ALLO is known to activate these receptors, which is why many women often feel lethargic or fatigued during the luteal phase. However, women with PMDD seem to experience the opposite. Instead of calming effects, ALLO seems to elevate neuron excitability and intensify emotional responses.

The Umeå research team set out to examine why this difference occurs. The study, published in Translational Psychiatry, measured the GABA-A receptor gene activity in immune blood cells collected from 29 women diagnosed with PMDD and 27 controls. The blood was harvested once during the calmer follicular phase and once during the symptomatic luteal phase. To investigate the receptor’s activity, the authors focused on the delta subunit of the receptor, which is known to be sensitive to chemical signals like ALLO.

Women with PMDD showed reduced gene activity of the delta subunit during the luteal phase, while the control women did not. In fact, in the women without PMDD, delta levels stayed the same between the follicular and luteal phase. This matters because, in theory, when ALLO levels rise during the luteal phase, receptors with the delta subunit should respond — but for women with PMDD, these receptors respond at a rate far lower than normal.

"Women with PMDD showed reduced gene activity of the delta subunit during the luteal phase, while the control women did not"

In addition to measuring receptor activity, the research team took brain scans of both groups of women during emotional tasks. Women who showed lowered activity of the delta subunit had higher activity in the amygdala—the brain’s central region for emotional processing—during these tasks. In other words, women with PMDD who showed lower levels of delta activity had a more reactive emotional response. The team suggests that this may be the biological explanation behind the mood symptoms associated with PMDD.

This study marks the first evidence of receptor changes reported across the menstrual cycle in women with PMDD. By exploring this mechanism further, pharmaceutical drugs and/or therapies could target this receptor to help lessen the symptoms of PMDD in women. While larger and further studies are needed on the subject, this study is a strong step forward in improving a condition that has long been minimized in medicine. 

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This article was written by Emma Reid and edited by Julia Dabrowska, with graphics produced by Neave Smith. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.