Review Kontekaki Aikaterini, Sinou Nikoleta, Filippou Dimitrios Dept. of Anatomy, Medical School, National and Kapodistrian University of Athens, Greece Research and Education Institute of Biomedical Science Correspondence Address: Aikaterini Kontekaki City: Piraeus, Greece, Email: katerinakontek@gmail.com doi: 10.5281/zenodo.18045796. . Abstract 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. Introduction Premenstrual Syndrome (PMS and Premenstrual Dysphoric Disorder (PMDD) are both associated with psychosomatic symptoms. According to the American College of Obstetricians and Gynecologists (ACOG), the former is a complex of distressing physical, behavioral, and affective symptoms among women of reproductive age, which usually occur the week before menstrual shedding and then fade away a few days later, whereas the latter is a pathological condition—a mood disorder that worsens during the second half of the cycle and is considered a severe or even disabling extended form of PMS [1]. The frequent confusion of these two terms may potentially lead to an underestimation of the severity of PMDD symptoms, which we propose often result in significant functional impairment. PMS appears in 3-8% of women in reproductive age, whereas PMDD affects 2% [2]. The inappropriate application of diagnostic criteria had previously led to an overestimation of the prevalence of PMDD [2]. The purpose of this study is to examine, through an extensive review of the literature, the various biochemical, genetic, and neural factors that contribute to the development of PMDD, while simultaneously defining it as a disorder distinct from simple premenstrual syndrome. Furthermore, we explored current therapeutic approaches and diagnostic protocols. A central component of our investigation is the analysis of PMDD symptomatology, which we aim to demonstrate is not merely a set of periodic psychosomatic complaints but rather a constellation of constant neuroendocrine disturbances rooted in its pathophysiology, ultimately leading to functional impairment. Materials and Methods The study was conducted during the month of November 2025. A thorough investigation was carried out using the published literature found in the PubMed and database, employing the following keywords: premenstrual dysphoric disorder (AND) fuctional impairment (1st search), premenstrual dysphoric disorder (AND) symptoms young women (2nd search), premenstrual dysphoric disorder (AND) neurology (3rd search), premenstrual dysphoric disorder (AND) endocrinology (4th search). To guarantee precision and completeness, data was collected through a standardized extraction form tailored to these keywords. The research was conducted in accordance with the PRISMA-ScR guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews), which provides a systematic framework for performing scoping reviews. The inclusion criteria were a) studies published in a journal, b) final-stage papers, c) research papers and only selected systematic reviews and meta-analyses, possessing particular interest and referring mainly to specific guidelines, and d) articles from 2016 until now. In accordance with the PRISMA guidelines, a total of 198 records were initially identified through the 4-stage search on PubMed: 1st search- 54 results, 2nd search- 99 results, 3rd search-19 results and 4th search- 26 results. After a thorough screening 155 studies were excluded due to irrelevance of the title and abstract to PMDD’s mechanisms or symptoms. A further examination of the 43 remaining studies led to exclusion of 19, due to exclusive focus on special groups Finally, 24 reports were assessed for eligibility, resulting in the exclusion of 174 articles in total. Thus, this specific article is founded on data sourced from 24 credible references (Figure 1). Results A thorough technique was used to evaluate the data according to the classification of the data mentioned above. While developing the themes, we took into consideration the mechanisms leading to PMDD and their effect on patient outcomes, as they are presented in all of the articles we selected as citations. In Table 1, we summarize the parts of the discussion included in the articles. Specifically, 20 articles referred to the vulnerability in steroids’ fluctuation as a causal factor for PMDD, while 10 and 4 articles introduced serotonin response and inflammation as significant determinants of the disorder. Moreover, 8 reports showed specific genetic variations on receptor molecules which can lead to impaired response. Through further examination, 5 reports indicate that neuroanatomical variations explain if not cause the symptomatology of PMDD. Those symptoms were analyzed in all articles, while 15 give also an analytical presentation of the diagnostic protocols for the disorder. At the same time, 14 articles address the already used therapeutic methods or introduce new ideas. Lastly, 12 studies show the relevance of PMDD with other conditions that seem to appear to PMDD women. Functional impairment was indicated as the overall result of PMDD symptomatology in 20 studies, which revealed the effect of PMDD pathophysiology on a variety of normal mechanisms. Discussion Progesterone and Estradiol. It is essential to get cleared that PMDD is not a matter of the quantity of the steroid hormones -since the levels of progesterone during the luteal phase do not differ between healthy women and women with the condition- [3], but a well-established problem of the response to the changes of these hormones [4]. Fluctuations in estradiol and progesterone destabilize mood in susceptible women. Defining PMDD as a neuroendocrinological disorder [5]. Progesterone passes through the blood-brain barrier and signals in the amygdala, hippocampus, hypothalamus, and frontal cortex [3], which are responsible for emotional and high-order cognitive responses. The problem seems to be attributed to the metabolite of progesterone, allopregnenolone, which acts as a strong positive modulator of the gamma-aminobutyric acid (GABA) receptor. Fluctuations on progesterone and thus allopregnenolone levels induce changes in the conformation of the GABA-A receptor sufficient to determine anxiety-like behaviors [3].As far as estradiol is concerned, it is correlated with enhanced centrality of the right posterior cingulate gyrus (rPCG) and with higher scores on emotional and cognitive control, implying that estradiol-related modulation of network hubs may contribute to improved well-being and adaptive behavior. The sharp decline of estradiol during the luteal phase makes PMDD women even more vulnerable to psychological roller coasters [6]. Serotonin. Women with PMDD exhibit atypical serotonergic functioning, including reduced serotonin transporter density, lower peripheral serotonin concentrations during the luteal phase, and an enhanced serotonergic responsiveness in the follicular compared with the luteal phase. In addition, ovarian sex steroids modulate central serotonin availability by acting on monoamine oxidase (MAO), the enzyme responsible for serotonin degradation [3]. Inflammation. Emerging evidence suggests that immune–inflammatory mechanisms may play a contributory role in PMS/PMDD. Fluctuations of estradiol and progesterone in the late luteal phase appear to promote oxidative and inflammatory activity, including increased production of prostaglandins, cytokines, and matrix metalloproteinases. Although studies have reported elevated peripheral inflammatory markers—such as interleukins, TNF-α, CRP, and complement factors—the overall findings remain inconsistent, with some studies demonstrating reduced antioxidant capacity and others showing no significant alterations. Recent research highlights the potential involvement of chemokines and a uterine brain signaling axis, as well as a central role for neuroinflammation mediated through altered GABAergic function [7]. Stress. Patients with PMDD exhibit blunted cortisol peaks during the periovulatory phase, highlighting a potential interaction between stress-response mechanisms and serotonergic regulation, and furtherly explaining the intensity of depressive symptoms observed in the premenstrual phase [8]. Furthermore, it is indicated by a recent translational study, that chronic stress weakens the normal regulatory responses of the hypothalamic–pituitary–adrenal (HPA) axis to progesterone withdrawal, which occurs in the late luteal period, resulting to abnormal responces [9]. Genetics. It is demonstrated that genes of the estrogen-sensitive ESC/E(Z) epigenetic complex are differentially expressed in women with PMDD, implicating dysregulated steroid-responsive gene silencing mechanisms [10]. The different response to estradiol leads to blunted endoplasmic reticulum stress response and altered intracellular calcium homeostasis, changes that may enhance neuronal excitability and reduce sensitivity to GABA-A receptor modulators. Additionally, copy number variations in GABRB2, a GABA-A receptor subunit gene, demonstrate a direct genetic link between PMDD and altered GABAergic signaling. Collectively, these insights support a model in which genetic and epigenetic factors confer heightened behavioral sensitivity to ovarian steroids and may guide the development of targeted therapeutic approaches [3]. Neuronatomy. It is suggested that specific functional connections within cortico–striatal–thalamic circuits mediate the association between emotion regulation difficulties and PMDD. Reduced grey matter volume in ventral posterior cortical regions, the cerebellum, and specifically in the amygdala and putamen, aligns with the hypothesis of disrupted top-down emotional regulation. Grey matter morphology seems to function as neurobiological biomarker of PMDD, enforcing the view that PMDD is not imited to a biochemical disturbance but rather concerns the central processor of stimuli, namely the central nervous system (CNS) [11]. According to Rotem et al, there are trait-like alterations in the functional connectome of women with PMDD, characterized by cortical hypoconnectivity—particularly in the anterior temporal lobe—and subcortical hyperconnectivity involving the basal ganglia and thalamus, as well as reduced network segregation and increased integration. These network abnormalities were present across both the symptomatic luteal and asymptomatic follicular phases, suggesting a stable neural vulnerability rather than a state-dependent change [12]. Therapeutic means. Current evidence indicates that the management of PMS and PMDD varies substantially according to symptom severity and functional impairment [3]. Mild PMS without functional limitations may respond to lifestyle-based or complementary interventions, whereas PMDD requires pharmacological or psychotherapeutic treatment. Nutrient-related interventions, including zinc supplementation, may exert beneficial anti-inflammatory, antioxidant, and neurotrophic effects, although evidence remains preliminary [3]. Among pharmacotherapies, selective serotonin reuptake inhibitors (SSRIs) demonstrate the strongest evidence base, with 60–70% of patients showing clinical improvement. Both continuous and luteal-phase dosing regimens are effective, though continuous administration may provide superior benefit in cases of severe symptomatology [13]. Combined estrogen–progesterone contraceptives [3], particularly monophasic formulations and those containing drospirenone, have also shown therapeutic potential, with one recent RCT indicating enhanced efficacy when combined with fluoxetine [3]. For refractory or severe presentations, GnRH agonists with add-back therapy may be considered [2] The new therapeutic approach modulates the action of allopregnenolone on the GABA receptor of the brain neurotrasmitters, given the plasticity of GABA-A receptor [14], using for exapmle the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase [15]. As for the mediation of the aggressive response of the frontal cortex, selective progesterone receptor modulator (SPRM) is suggested [16]. Although the evidence for psychological interventions remains limited, preliminary data suggest that internet-based cognitive-behavioral therapy can meaningfully reduce PMS-related symptom burden [2]. Symptoms/ Diagnosis. It has been observed that cognitive shifts occur throughout the menstrual cycle; however, these changes are markedly more pronounced in women suffering from PMDD [17]. Specifically, women with PMDD show significant increases in negative affect and rumination and decreases in positive affect and self-acceptance toward the end of the cycle [7]. The difference between PMS and PMDD does not lie on the symptoms complex, but on its severity. Haussman et al suggests that PMS and PMDD are connected with a wide range of emotional, behavioral, and cognitive manifestations that emerge during the luteal phase and tone down in the follicular phase [2]. Characteristic physical symptoms include mastodynia, headaches, abdominal bloating, fatigue-like complaints, and hot flashes. On average, symptoms persist for approximately six days per month, with peak severity occurring from four days before to three days after the onset of menstruation. The affective symptoms, which frequently predominate, include depressed mood, irritability, anxiety, feelings of tension, anger outbursts, increased appetite up to binge-eating episodes, rejection sensitivity, and loss of interest [2]. Age, age at menarche, income, menstrual cycle, menstrual symptoms, physical activity, and caffeine intake are indicated as independent influencing factors of PMDD in adult working women [18]. With regard to hereditary risk factors, genetic polymorphisms in the ESR1 gene, which encodes the estrogen receptor-α, are being discussed [2]. Prior traumatic events, a history of mental disorders, peripartum depression, obesity, smoking, alcohol use, and heavy drinking are also cosidered risk factors for PMDD [19]. The major symptoms of PMDD function as diagnostic markers in clinical practice. Currently, PMDD is listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a separate entity under Depressive disorders, with 4 diagnostic criteria. If at least 1 of these 4 criteria is met, the diagnosis leads to PMS [5]. The cut-off point between PMS and PMDD lies on the presence of more than 5 symptoms of the following [2]: depression, hopelessness, affective lability, anger and irritability, decreased interest in usual activities, short attention span, lethargy or lack of energy, change in appetite (overeating and cravings), insomnia or hypesomnia, subjective sense of being overwhelmed, other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of bloating, or weight gain [19]. These symptoms establish the 1st Criterion, while the rest define if the severity of the symptoms interferes with social, sexual, occupational functioning, if they are discretely related to the menstrual cycle and if they are confirmed by prospective daily ratings [20]. A Meta-Analysis held in 2021 indicates that women with PMDD are almost seven times at higher risk of suicide attempt and almost four times as likely to exhibit suicidal ideation compared to women with no PMDD or PMS, while women with PMS were not in a risk for suicidal attempt [21]. Moreover, it is shown that women with PMDD appear to have an increased risk for comorbid attention deficit hyperactivity disorder (ADHD) [22], extending the criterion-symptom of “short attention span” and entering the field of a more generalized functional impairment. Functional impairment. In the past, many studies evaluated the cognition in PMDD focusing on memory and attention, neglecting the functional part which refers to higher-order cognitive processes such as monitoring, organizing, flexibility, shifting, and planning [23]. At the same time there is also the view that it is not a matter of interest, but a matter of occupational competence that makes women with PMDD less functional during the luteal phase [24]. According to a 2022 study, women with PMDD exhibit reduced executive functioning during the late luteal phase. This impairment was associated with diminished use of cognitive reappraisal strategies (the ability to regulate emotions uning logical patterns) and higher levels of depressive symptoms.Among the examined factors, inattention showed the strongest association with PMDD and with late-luteal-phase functional impairment, even after accounting for depressive symptoms [23]. These observations suggest that functional impairment is an inevitable part of the PMDD-symptom-complex concerning cognitive and emotional dimensions [17]. An Ecological Momentary Assessment study of 2020 highlights the exacerbation of symptoms during the late luteal (LL) phase as the distinguishing feature between PMDD and other mood disorders. PMDD women report highest levels of rumination and lowest levels of self-acceptance during the late luteal phase, while healthy women do not show such cycle-dependent variations of mood and cognitions. Moreover, it was shown that PMDD is connected with a reciprocal relationship between rumination and NA, especially in the late luteal phase. However, the truly noteworthy finding of the study is that women suffering from PMDD tend to rumination as a response to negative affect independently from their cycle phase. Rumination appears as a constant characteristic of PMDD women compared to the non-affected ones [7], implying a stable functional impairment in terms of emotional control. Further studies have also indicated that PMDD is linked to avoidant personality disorder (for women above 30), impulsive-aggressive personality traits, depressive and manic symptoms indepenent of the menstrual cycle [20], probably due to theenhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex [16]. Conclusions In conclusion, PMDD appears as a result of multiple factors that may act, either as independent risk factors, or synergistically with one another. The disorder’s pathophysiology isconsidered to reflect an impaired neural sensitivity to the endocrine fluctuations of the menstrual cycle [6], stemming from a problematict response to estradiol and progesterone. Serotonergic vulnerability [3], genetic predisposition [10], and exposure to stress and inflammation [7],[8],[9] could also play a significant role in the development of PMDD. Even anatomical variations have now been associated with PMDD symptomatology [11] [12]. Importantly, the clinical presentation that follows this pathophysiological pattern extends far beyond the typical premenstrual discomfort and it manifests as a broader pattern of functional impairment. The molecular mechanisms implicated in PMDD explain the disruption of overall functioning [23], supporting the view that PMDD should not be considered merely a cycle-dependent mood disorder, but rather a condition characterized by permanent and multidimensional dysfunction [1]. References 1. Sayed SH, AL-Mohaithef M, Ibrahim EM, Elsayed EA. Premenstrual syndrome and premenstrual dysphoric disorder: Symptoms severity, functional impairment, and associated factors: A Saudi cross-sectional study. Journal of Education and Health Promotion. 2025 May;14(1). 2. Haußmann J, Goeckenjan M, Haußmann R, Wimberger P. [Premenstrual syndrome and premenstrual dysphoric disorder-Overview on pathophysiology, diagnostics and treatment]. Der Nervenarzt [Internet]. 2024 Mar 1;95(3):268–74. Available from: https://pubmed.ncbi.nlm.nih.gov/38393358/ 3. Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Faculty Reviews [Internet]. 2022 Apr 28;11(11). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9066446/ 4. Stiernman L, Dubol M, Comasco E, Sundström-Poromaa I, Boraxbekk CJ, Johansson M, et al. Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids. Translational Psychiatry. 2023 Apr 14;13(1). 5. Schiller CE, Johnson SL, Abate AC, Schmidt PJ, Rubinow DR. Reproductive Steroid Regulation of Mood and Behavior. Comprehensive Physiology. 2016 Jun 13;6(3):1135–60. 6. Liparoti M, Troisi Lopez E, Sarno L, Rucco R, Minino R, Pesoli M, et al. Functional brain network topology across the menstrual cycle is estradiol dependent and correlates with individual well‐being. Journal of Neuroscience Research. 2021 Jun 10;99(9):2271–86. 7. Beddig T, Reinhard I, Ebner-Priemer U, Kuehner C. Reciprocal effects between cognitive and affective states in women with Premenstrual Dysphoric Disorder: An Ecological Momentary Assessment study. Behaviour Research and Therapy. 2020 Aug;131:103613. 8. Hoffmann K, Zsido RG, Villringer A, Hesse S, Sabri O, Engert V, et al. Exploring the cortisol awakening response in premenstrual dysphoric disorder and in healthy females across the menstrual cycle. The British journal of psychiatry : the journal of mental science [Internet]. 2025 Oct;1–9. Available from: https://pubmed.ncbi.nlm.nih.gov/41208395/ 9. Islas-Preciado D, López-Rubalcava C, Estrada-Camarena E, de Gortari P, Castro-García M. Effect of chronic unpredictable stress in female Wistar-Kyoto rats subjected to progesterone withdrawal: Relevance for Premenstrual Dysphoric Disorder neurobiology. Psychoneuroendocrinology [Internet]. 2023 Sep 1 [cited 2023 Jul 25];155:106331. Available from: https://www.sciencedirect.com/science/article/pii/S0306453023003098 10. Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, et al. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Molecular Psychiatry. 2017 Jan 3;22(8):1172–84. 11. Dubol M, Stiernman L, Wikström J, Lanzenberger R, Neill Epperson C, Sundström-Poromaa I, et al. Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification. Translational Psychiatry. 2022 Jun 15;12(1). 12. Dan R, Reuveni I, Canetti L, Weinstock M, Segman R, Goelman G, et al. Trait-related changes in brain network topology in premenstrual dysphoric disorder. Hormones and Behavior. 2020 Aug;124:104782. 13. Jespersen C, Mette Petri Lauritsen, Frokjaer VG, Schroll JB. Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder. Cochrane library [Internet]. 2024 Aug 14;2024(8). Available from: https://pubmed.ncbi.nlm.nih.gov/39140320/ 14. Sikes-Keilp C, Rubinow DR. GABA-ergic Modulators: New Therapeutic Approaches to Premenstrual Dysphoric Disorder. CNS drugs [Internet]. 2023 Aug 1;37(8):679–93. Available from: https://pubmed.ncbi.nlm.nih.gov/37542704/ 15. Bixο M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, et al. Treatment of premenstrual dysphoric disorder with the GABA A receptor modulating steroid antagonist Sepranolone (UC1010)—A randomized controlled trial. Psychoneuroendocrinology. 2017 Jun;80:46–55. 16. Kaltsouni E, Fisher PM, Dubol M, Hustad S, Lanzenberger R, Frokjaer VG, et al. Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator. Neuropsychopharmacology. 2021 Apr 29;46(8):1460–7. 17. Rabbani H, Irfan S, Khanum S. Pre and Post Menstruation Cognitive Functioning in Women with remenstrual Dysphoric Disorder, Premenstrual Syndrome and Controls: A Quasi Experimental Study. BMC women’s health [Internet]. 2025 Summer;25(1):559. Available from: https://pubmed.ncbi.nlm.nih.gov/41239306/ 18. Wu H, Yang Y, Shen W. Prevalence and Correlations of Premenstrual Dysphoric Disorder: A Sample of Adult Working Women. Actas Españolas de Psiquiatría [Internet]. 2024 Oct 5;52(5):678–85. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11474960/ 19. Mishra S, Elliott H, Marwaha R. Premenstrual Dysphoric Disorder [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://pubmed.ncbi.nlm.nih.gov/30335340/ 20. Naik SS, Yadav Nidhi, Kumar K, Grover S. Diagnostic validity of premenstrual dysphoric disorder: revisited. Frontiers in global women’s health [Internet]. 2023 Nov 27;4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10711063/ 21. Prasad D, Wollenhaupt-Aguiar B, Kidd KN, de Azevedo Cardoso T, Frey BN. Suicidal risk in women with premenstrual syndrome and premenstrual dysphoric disorder: A systematic review and meta-analysis. Journal of Women’s Health. 2021 Aug 20;30(12). 22. Lin PC, Long CY, Ko CH, Yen JY. Comorbid Attention Deficit Hyperactivity Disorder in Women with Premenstrual Dysphoric Disorder. Journal of Women s Health [Internet]. 2024 Jun 5;33(9):1267–75. Available from: https://pubmed.ncbi.nlm.nih.gov/38836765/ 23. Lin PC, Ko CH, Yen JY. Early and Late Luteal Executive Function, Cognitive and Somatic Symptoms, and Emotional Regulation of Women with Premenstrual Dysphoric Disorder. Journal of Personalized Medicine. 2022 May 18;12(5):819. 24. Pekçetin S, Özdinç S, Ata H, Can HB, Sermenli Aydın N, Taş Dürmüş P, et al. Perceived occupational competence and value among university students with premenstrual dysphoric disorder. British Journal of Occupational Therapy. 2021 May 24;85(5):030802262110209.