Estrogen, the Menstrual Cycle, and the Female Brain: Why Irregular Cycles Belong in Neuroscience

For decades, neuroscience and brain research have excluded women with irregular menstrual cycles—such as absent, infrequent, or unpredictable periods—on the assumption that their fluctuating hormones would “confound” data. This practice may have simplified study design, but as Heller, Christensen, Murata, and colleagues argue in Nature Medicine (2025), it has also blinded science to valuable biological insights.

Menstrual cycle irregularities are not random noise—they are important clinical signals that need to be looked at. They often indicate hormone deficiencies and disruptions in the hormonal orchestra that regulates not only the reproductive system but also the brain. The key conductor of this orchestra? Estrogen.

Estrogen: The Link Between Cycle Regularity and Brain Health

The menstrual cycle is orchestrated through the hypothalamic–pituitary–gonadal (HPG) axis. The brain (hypothalamus and pituitary) communicates with the ovaries to regulate the production of estrogen and progesterone each month.

Estrogen—particularly estradiol (E2)—is not only essential for triggering ovulation and regulating the menstrual cycle but also acts as a woman’s most powerful neuroactive hormone. It modulates neurotransmitters like serotonin, dopamine, norepinephrine, and GABA; enhances synaptic plasticity; supports myelination; and maintains cerebral blood flow.

When cycles become irregular—it is a signal that estrogen is low, and the lower it falls, the more irregular the cycle and brain function become. With this irregularity comes a slew of conditions associated with the brain.

Brain Research Without Estrogen’s Full Story Is Incomplete

Neuroimaging studies in women with regular cycles have shown that estrogen alters brain network connectivity—particularly in the default mode network (linked to self-referential thought), the salience network (emotion detection), and the central executive network (working memory and decision-making).

If regular-cycle estrogen patterns affect brain wiring so profoundly, then what happens when estrogen is insufficient? The answer could shed light on why women with menstrual irregularities experience higher rates of mood disorders, cognitive changes, and even neurodegenerative risk. If estrogen influences brain function and menstrual cycles so much, is it smart to exclude estrogen from the research? By excluding women with irregular menstrual cycles, research misses a critical opportunity to study how estrogen deficiency shapes brain health.

The Clinical and Public Health Relevance

From a medical standpoint, menstrual cycle irregularities are red flags for neuroendocrine imbalance secondary to hypoestrogenism. Low or declining estrogen can:

• Reduce serotonin activity, increasing vulnerability to depression and anxiety.
• Impair dopamine regulation, affecting motivation and focus.
• Lower acetylcholine function, influencing memory and learning.
• Disrupt cerebral blood flow and energy metabolism, contributing to brain fog and fatigue.

For women in their 30s and 40s, the symptoms of perimenopause are those of estrogen deficiency. Understanding this allows women an opportunity for early restorative intervention. The sooner women restore estrogen, the less likely they are to experience what many refer to as the side effects of perimenopause.

For younger women, cycle changes often point to metabolic issues, a high processed food diet, chronic stress effects, or endocrine-disrupting exposures—all of which influence estrogen production and have brain implications.

Why Inclusion Matters

Heller et al. call for a paradigm shift: instead of excluding women with irregular cycles, researchers should treat these patterns as meaningful variables. This approach can:

1. Reveal brain–body mechanisms unique to hormone-disrupted states.
2. Improve prevention and treatment for mental health, cognitive decline, and neuroendocrine disorders.
3. Promote health equity, ensuring findings apply to the real-world diversity of women’s experiences.

Final Thoughts

Menstrual cycle irregularities are not an inconvenience—they are data. Estrogen is the critical bridge linking reproductive health to brain health, and any serious attempt to understand the female brain must account for its presence, absence, or dysregulation.

By integrating women with irregular cycles into neuroscience, we gain not only scientific accuracy but also the potential to transform care for millions of women whose symptoms of estrogen deficiency are too often dismissed.

_Reference:

_{Heller, C., Christensen, E., Murata, E.M. et al. Why menstrual cycle irregularities belong in brain research. Nat Med (2025).}