Chronic stress, immune imbalance, and thyroid dysfunction are deeply interconnected. This forms a stress–immune–thyroid triad where each system influences the others, affecting energy, mood, and resilience. Research shows that targeted support—including adaptogens, micronutrients can help restore communication across this network. Rather than offering quick fixes, this systems-based approach addresses underlying feedback loops, combining clinical insight, patient engagement, and supportive lifestyle practices to rebuild physiological balance and improve well-being over time.
Ashlyn Zikmund, ND
Introduction
Premenstrual syndrome (PMS) affects nearly half of menstruating women worldwide, yet its impact is often underestimated and its biology misunderstood. It is defined by recurrent physical and emotional luteal-phase symptoms that resolve with menstruation, with the most common PMS symptoms being irritability, mood swings, bloating, breast tenderness, and fatigue. These symptoms can significantly impair quality of life, interfere with relationships, and effect overall well-being for many individuals. Its more severe counterpart, premenstrual dysphoric disorder (PMDD), affects approximately 3-8% of menstruating individuals, and is associated with more severe psychological distress. [1] Despite its prevalence, the precise biological mechanisms underpinning PMS and its symptoms are not fully understood, prompting ongoing research investigating the relationship between menstrual cycle changes and the central nervous system on this multifaceted condition.
Hormonal Influence on PMS
The menstrual cycle is broken up into two main phases, the follicular phase and the luteal phase, with ovulation being the main event that divides the two phases. Throughout the menstrual cycle, hormone levels, primarily estrogen and progesterone, fluctuate, with the most notable changes appearing in the luteal phase. So, let’s break down these hormonal changes.
- Early luteal phase: Following ovulation, estrogen levels drop significantly compared to their preovulatory peak, while progesterone levels begin to rise and peak in the mid-luteal phase.
- Late luteal phase: Drop in both progesterone and estrogen levels in the absence of conception.
Previously it was hypothesized that low levels of progesterone in the late luteal phase could be the cause of PMS symptoms; however, women with PMS cannot routinely be distinguished based on hormone levels. [2] The onset of symptoms during the luteal phase underscores the hormonal basis of PMS and PMDD, though research emphasizes a more complex interaction between the hormonal fluctuations and the central nervous system.
Neurotransmitter Regulation
Of particular interest is the progesterone metabolite, allopregnanolone, which interacts with gamma-aminobutyric acid A (GABAA) receptors. The GABA system is an inhibitory system in the CNS and GABAA receptor modulators enhance anxiolytic, sedative and anesthetic effects. It is hypothesized that individuals with PMS, and most notably with PMDD, may have altered GABAA receptor sensitivity, which may explain the onset of symptoms in the luteal phase when progesterone and its metabolite allopregnanolone are most significantly fluctuating. [3]
One study hypothesized that women with PMDD may have increased conversion of progesterone to allopregnanolone due to findings that PMDD subjects had statistically significantly increased luteal allopregnanolone and lower cortisol compared to control subjects. [4]
Additionally, a double-blind placebo-controlled cross over study found that administration of dutasteride, a 5 alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, resulted in statistically significant reductions in PMDD symptoms but had no effect on control subjects. [5] Further, individuals taking leuprolide, a GnRH agonist that interferes with ovarian hormone production, experienced a recurrence of PMS symptoms once re-administered progesterone. [6]
Altered serotonin activity has also been implicated in PMS, particularly due to the efficacy of selective serotonin reuptake inhibitors (SSRIs) in symptom relief, as well as the influence of estrogen and estrogen receptors on serotonin transmission. [7] Decreased serotonergic transmission during the luteal phase may underlie and or exacerbate PMS symptoms, especially in the presence of altered GABA sensitivity. [1]
Immune dysregulation
Evidence suggests that psychological and emotional stress can stimulate the peripheral immune system and release pro-inflammatory cytokines similarly to when the body encounters physical injury, illness or infection. [9] Research reveals that individuals with PMS and PMDD experience a heightened stress response during the luteal phase and therefore, there may be a connection between PMS/PMDD and inflammation.
A cross-sectional analysis using baseline data from the longitudinal Study of Women’s Health Across the Nation found that high-sensitive c-reactive protein (hs-CRP), a marker of inflammation, was associated with certain PMS symptoms, suggesting that markers of inflammation may be helpful biomarkers and therapeutic targets for affected individuals. [10]
Further, inflammation plays a role in GABAergic activity, thus increased inflammatory activity may interfere with the GABA response and play a role in the altered GABA sensitivity previously mentioned. [11]
Summary
PMS is a multifactorial condition primarily rooted in the interplay between fluctuating levels of ovarian hormones and central nervous system involvement, especially serotonin and GABA systems. Emerging research is also pointing to inflammation as a contributing factor, potentially amplifying neurotransmitter dysregulation. These interactions affect mood, pain perception, and behavior, disrupting daily life and impacting overall well-being. These findings highlight the need for a more integrated understanding of PMS that goes beyond hormones alone and considers the full physiological picture.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Ashlyn Zikmund, ND is a licensed naturopathic physician with a focus on therapeutic strategy, clinical integration, and root-cause care. With extensive experience in both private practice and multidisciplinary healthcare teams, she specializes in complex chronic conditions, including endocrine and metabolic disorders. She sees patients in person and virtually at Natural Paths to Wellness in Camp Hill, Pennsylvania.