What causes PMDD and why is it hard to function?

Introduction: Premenstrual Dysphoric Disorder (PMDD) is an abnormal condition that extends beyond the framework of typical premenstrual symptoms and frequently results in significant functional impairment. Methods: A scoping review was conducted in November 2025 following PRISMA-ScR guidelines. Four structured searches were performed in PubMed using predefined combinations of keywords related to PMDD, functional impairment, neurobiology, endocrinology, and symptomatology. Inclusion criteria encompassed peer-reviewed journal articles and final-stage papers published between 2016–2025. Out of 198 initially identified records, 24 met eligibility criteria and were included in the final synthesis. Results: PMDD consistently emerged as a disorder rooted in altered neural sensitivity to ovarian steroid fluctuations, rather than abnormal hormone levels. Evidence highlighted dysregulated GABAergic and serotonergic signaling, impaired stress-response mechanisms, increased inflammatory activity, and trait-like disruptions in cortico-striatal-thalamic connectivity. Genetic and epigenetic contributions—including variations in GABA-receptor subunit genes and ESC/E(Z) complex dysregulation. Symptomatically, PMDD was associated with marked affective lability, cognitive dysfunction, and decreased executive functioning, resulting to an overall functional impairment. Diagnostic protocols and therapeutic options (SSRIs, hormonal therapies, neurosteroid antagonists, and cognitive-behavioral interventions) were described across studies. Aim: The aim of this review is to synthesize current evidence on the biochemical, genetic, neuroendocrine, immunological, and neuroanatomical factors contributing to PMDD, to clarify functional impairment as the main inevitable result of the disorder. Keywords: Premenstrual Dysphoric Disorder; Neuroendocrinology; Serotonin; GABA Receptors; Functional Impairment.

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