Post COVID syndrome (PCS) represents a significant global health challenge affecting an estimated 6–10% of COVID-19 survivors (1, 2). This condition is characterized by persistent or new symptoms that continue beyond 4 weeks following acute SARS-CoV-2 infection and are not attributable to another disease, with fatigue being among the most commonly reported and debilitating manifestations (3). Although the molecular mechanisms underlying PCS are not fully understood yet, autoimmunity has been shown to be a hallmark characteristic of this disease (4).

The prevalence and impact of PCS vary considerably across different populations, with emerging evidence suggesting important sex-based differences in symptom presentation and severity (5). Understanding such sex and gender specific differences in PCS is crucial for developing targeted therapeutic approaches and ensuring equitable healthcare delivery.

Recent neuroimaging research identified brain network abnormalities associated with mental fatigue that involve cortical–subcortical networks within frontal, limbic, basal ganglia and parietal structures (6). While acute COVID-19 showed male predominance in hospitalization, severe outcomes and mortality (7, 8), PCS appears to disproportionately affect women, and merging evidence suggests that female predominance in PCS may be linked to sex-specific autoimmune dysregulation, including higher autoantibody levels, enhanced B-cell reactivity, and skewed inflammatory responses in women with persistent symptoms (9). Previous studies demonstrated that female patients are significantly more likely to develop PCS overall, with an up to 50% increased risk compared to males (10, 11). However, the specific manifestation of fatigue-related symptoms and their impact on quality of life in women with PCS remains inadequately characterized.

Fatigue in PCS encompasses not only physical exhaustion, but hallmark symptoms also include cognitive fatigue, brain fog, sleep disturbances, and post-exertional malaise (12, 13). These symptoms can severely impact daily functioning, work productivity, and overall quality of life (14).

The present study aimed to examine gender-based differences in fatigue-related symptoms among individuals with PCS, focusing specifically on the frequency, severity, and quality of life impact of these symptoms, and a possible relation to menstrual cycle phases. By analyzing data from a large German cohort, we sought to provide evidence-based insights that can inform clinical practice and guide future research directions in women’s health and PCS management.

This study provides findings of significant gender-based differences in fatigue-related symptoms among individuals with PCS, with females experiencing both higher prevalence and greater severity of these debilitating symptoms. The majority of menstruating persons with PCS in our survey reported moderate or strong association of their menstrual cycle on fatigue symptoms. Although our exploratory study cannot establish causality between gender and PCS-related symptoms, these findings have important implications for clinical care, research priorities, and public health approaches to PCS management.

The observed female predominance in fatigue-related symptoms aligns with broader patterns seen in other fatigue-related conditions such as chronic fatigue syndrome and fibromyalgia (20, 21). The significantly higher rates of fatigue, brain fog, and sleep disturbances in women with PCS suggest potential gender-specific mechanisms underlying these symptoms.

Our findings on self-reported menstrual cycle dependent symptom changes in PCS align well with previous research on the influence of female reproductive health on PCS symptoms (22, 23). A recent paper by Maybin et al. demonstrated that PCS symptoms fluctuate across the menstrual cycle, with severity peaking during perimenstrual and proliferative phases (24). Their research indicates this relationship stems from peripheral and endometrial inflammation. Our observation of higher fatigue severity in women with PCS and cyclical worsening of fatigue symptoms corroborates their findings suggests that hormonal fluctuations and associated inflammatory processes amplify fatigue and worsen HRQoL in affected women.

Although not assessed in our study, our results hint to several biological factors, that may contribute to these differences. Hormonal influences throughout the menstrual cycle, particularly estrogen and progesterone fluctuations, can significantly impact energy levels, sleep patterns, and cognitive function (25, 26). The hypothalamic–pituitary–adrenal axis, which plays a crucial role in stress response and energy regulation, shows sex and gender-specific differences that may influence fatigue and susceptibility to fatigue related syndromes (27, 28).

Neuroinflammatory processes and autoimmunity, increasingly recognized as central to PCS pathophysiology, also exhibit sex/gender-specific patterns (4, 29, 30). This may be due to differential immune cell activation and be associated with distinct risk profiles for postviral sequalae and neurological and neurodegenerative diseases in women vs. men (4, 31–33).

Our findings suggest several important clinical implications. In our cohort, HRQoL scores were low, particularly among participants experiencing fatigue and among women. These scores were below the reference values reported for the older German population but comparable to index values observed in patients with rheumatoid arthritis (34, 35). Sex/gender differences in HRQoL have been described for different diseases (36), but it remains unclear whether this is primarily due to higher disease burden or other factors. The substantially poorer HRQoL scores among female survey participants with PCS in our cohort - surpassing a minimally important difference when compared to male respondents - highlight the urgent need for sex and gender-sensitive clinical approaches (37). Healthcare providers should be aware of the higher likelihood and severity of fatigue symptoms in female PCS patients and adapt management strategies to possible symptom worsening during specific menstrual phases. To our current knowledge, such interventions might include specialized fatigue management programs, cognitive behavioral therapy adapted for PCS-related cognitive symptoms, or hormonal evaluations in selected cases (38–41).

Our findings underscore the ongoing need for research to systematically examine sex/gender as a central biological variable in PCS, as we focused on the self-reported gender. Mechanistic analyses investigating biological aspects such as hormonal influences, particularly longitudinal relationships between hormonal factors and symptom severity, will provide further insight into PCS pathophysiology and may disclose novel treatment targets.

Several limitations of our work should be acknowledged. Although women are more likely to experience PCS (2), the predominantly female composition of our cohort may reflect selection bias, which limits the generalizability of our findings. Women may be more likely to seek care and take differential approaches to participate in health research (42, 43), and the dominance of female participant might lead to an overestimation of gender-specific differences. Also, we asked participants about their self-perceived gender and not biological sex, which is non-aligning in an estimated 0.4–1.6% of individuals (16, 17). The analysis of gender identity represents a methodological simplification, especially when describing the non-binary group, and should be taken into account when interpreting our results in the context of work that was performed on sex and not gender stratified cohorts. Also, the influence of important factors known to differ significantly between genders such as socioeconomic status, caregiving responsibilities, and mental health (44) were not or only in part analyzed in and should be assessed in future studies focusing on gender specific disease burden in PCS. The self-reported nature of symptom data introduces potential reporting bias, though validated questionnaires were used to minimize this concern. Fatigue severity was dichotomized at the median for the primary analyses due to the absence of validated clinical thresholds for post-COVID symptom severity. This approach may influence prevalence estimates and attenuate or exaggerate effect sizes. To address this, sensitivity analyses using continuous symptom scores were performed and yielded consistent results. The cross-sectional design prevents causal inferences about gender-related mechanisms underlying fatigue differences. Also, we did not ask for further factors crucially impacting reproductive and female health such as for example endometriosis, which was recently shown to significantly influence PCS symptoms as well (45). Our cohort was well educated, with 61.8% with a college-preparatory qualification, which makes the generalization to persons with lower education or socioeconomic status challenging.

Our findings underscore the critical need for research to systematically examine gender as a central biological variable in PCS. Future investigations should prioritize longitudinal studies examining hormonal fluctuations across menstrual cycles and their relationship to symptom severity. Also, the influence of factors such as hormonal contraception, detailed symptoms of (peri-) menopause, or conditions such as endometriosis should be studied, as well as biomarkers that account for sex-specific inflammatory and neuroendocrine responses. Despite its limitations, our study provides compelling evidence that gender-based differences in PCS-related fatigue are not merely quantitative but reflect fundamental biological variations that demand distinct clinical approaches. The substantial symptom burden experienced by females, compounded by menstrual cycle-dependent fluctuations affecting two-thirds of menstruating persons with PCS, necessitates a paradigm shift from one-size-fits-all protocols to precision medicine approaches that integrate reproductive health into PCS management. Only through recognizing and addressing these gender-specific patterns can we move beyond symptomatic treatment toward truly personalized therapeutic strategies that acknowledge the unique biological realities of women with PCS, ultimately transforming post COVID care from a universal model that inadvertently disadvantages women to one that provides equitable, effective treatment tailored to each patient’s biological and hormonal context.