Abstract
Introduction: Postural orthostatic tachycardia syndrome (POTS), a specific form of orthostatic intolerance (OI), is a prevalent autonomic dysfunction in adolescents associated with significant physical and psychosocial challenges. Limited research has explored the impact of these conditions on gender-diverse youth. This study examines the psychological and functional factors affecting non-binary and transgender adolescents with autonomic dysfunction. Methods: A two-year retrospective analysis (May 2022–May 2024) was conducted with adolescents (<19 years old) diagnosed with autonomic dysfunction based on the ICD code of POTS or OI or dysautonomia. Participants completed Patient Health Questionnaire-Adolescent (PHQ-A), Generalized Anxiety Disorder-7 (GAD-7), Functional Disability Inventory (FDI), Somatic Symptom Scale-8 (SSS-8), and Pain Catastrophizing Scale (PCS). Data were analyzed using descriptive statistics and chi-square tests to compare transgender and non-binary cohorts. Results: The study included 23 individuals: 12 non-binary (mean age 17), 9 transgender males (mean age 17), 1 transgender female (age 16), and 1 individual listed as ‘other.’ No statistically significant differences were found between groups. Transgender youth had higher mean scores for depression (9.3 vs. 7.8), anxiety (11.2 vs. 9.9), and PCS (21.2 vs. 20.9). Non-binary youth had higher scores for somatic symptoms (16.5 vs. 14.7) and functional disability (25.8 vs 20.7). Conclusion: Although no significant differences were observed, preliminary findings suggest higher levels of anxiety and pain-related distress in gender-diverse youth compared to published data on patients with POTS. Further research with a larger sample size to better detect significant differences between groups of patients, including cisgender cohorts, is warranted to address the unique needs of these populations.
Keywords: Autonomic dysfunction, adolescent medicine, children and adolescents with complex medical needs, orthostatic intolerance (OI), postural orthostatic tachycardia syndrome (POTS), transgender, non-binary, gender-diverse, mental health, functional disability, screening, pediatrics
Introduction
OI is a common form of autonomic dysfunction observed in adolescents, with POTS being a specific subtype, both of which significantly impact both physical and psychosocial functioning1–4. These conditions affect approximately 1% of individuals, with a majority of those impacted being teenagers. Adolescents with POTS and OI often experience a range of debilitating symptoms, including dizziness, fatigue, gastrointestinal dysfunction, headaches, cognitive difficulties, and rapid heart rate. These symptoms disrupt daily activities, resulting in missed school days, a reduction in physical activity, and withdrawal from social interactions, all of which contribute to a decreased quality of life5,6. Typically, POTS and OI present around puberty7, with the peak age of onset being approximately 14 years old8–11. The incidence of these disorders has notably increased following the COVID-19 pandemic, with a significant overlap among long COVID, OI, and POTS.
The underlying physiological changes in autonomic dysfunction, particularly those involving orthostatic intolerance, are primarily related to the improper constriction of peripheral blood vessels, leading to peripheral pooling of circulating blood. This, in turn, causes a reduction in stroke volume and compensatory postural tachycardia. Despite this compensatory mechanism, there is inadequate cerebral circulation while upright, resulting in hypoperfusion and contributing to dizziness, light-headedness, and cognitive dysfunction12,13. These symptoms mark the onset of orthostatic intolerance, which further impairs exercise capacity. As physical activity decreases, deconditioning occurs, initiating a cycle of worsening autonomic dysfunction as the body continues to experience sympathetic activation due to insufficient exercise9.
While the initial decline in physical functioning in these patients is related to the physiological changes of orthostatic intolerance, over time, cardiac deconditioning sets in due to reduced activity levels, making it increasingly difficult for adolescents to engage in physical exercise. This issue is particularly problematic for high-achieving teenagers, who often struggle to pace themselves and, instead, tend to push their limits, resulting in “push and crash” cycles14. A common experience is that the same physical activity that once felt easy may now lead to a prolonged post-exertional malaise (PEM), which causes anxiety about physical exertion itself. It is worsening of symptoms following even minor physical or mental exertion that would have been tolerated previously. Symptoms typically worsen 12 to 48 hours after activity. PEM can last for days or even weeks.14 This fear often leads to further avoidance of physical activity. Additionally, autonomic dysfunction often causes gastrointestinal symptoms15. These symptoms contribute to poor nutrition and fluid intake, with individuals frequently skipping meals and failing to drink enough water. This can lead to volume depletion, which can further exacerbate orthostatic intolerance and fatigue. Combined with a tendency to nap during the day, this results in poor nighttime sleep and prevents full recovery. These multifactorial physical processes exacerbate the overall functional decline.
Additionally, the prolonged diagnostic odyssey16–18 and delays that many patients face before receiving a proper diagnosis can also worsen functioning4,19. Without a clear understanding of their condition, these adolescents experience heightened anxiety and uncertainty regarding their health. They struggle to make sense of their symptoms, which can lead them to skip school and reduce physical activity. They lack the knowledge to pace themselves. Unfortunately, the lack of medical supervision and appropriate care only worsens their functional decline3,10,20. This frustration and worry about their health often amplify anxiety and depressive symptoms, further hindering their ability to manage daily life. The link between depression and functional disability is well-documented in the literature21–23.
While there is growing recognition of the impact of POTS and OI on adolescents, most research in this area has focused predominantly on cisgender youth, leaving a significant gap in our understanding of how these conditions affect gender-diverse populations, such as transgender and non-binary adolescents. Gender-diverse youth face distinct challenges, including those related to hormone use, identity-based discrimination, and social stress24,25. These factors can significantly influence their experiences with POTS, OI, and other forms of autonomic dysfunction. The unique challenges of gender-diverse adolescents may alter how their symptoms are perceived, reported, and managed, which could help explain why some individuals in these populations struggle to access appropriate care and support.
Sex plays a significant role in the incidence of autonomic dysfunction, with females being at notably higher risk than males. This gender disparity is likely influenced by hormonal factors, which may help explain some of the variation in autonomic dysfunction prevalence between sexes. Understanding the impact of hormones is further complicated by the experiences of transgender and non-binary individuals whose symptoms and treatment outcomes can be influenced by hormonal manipulation. Studying these populations at various stages of hormonal transition could provide valuable insights into how hormonal changes affect autonomic dysfunction, enhancing our understanding of the condition across all patients, regardless of sex or gender identity.
To address this gap, we explored how gender identity intersects with the biological and psychological stressors associated with autonomic dysfunction. By understanding these intersections, we can develop more effective and inclusive care strategies that take into account the unique experiences of gender-diverse adolescents. The aim of this study is to take an initial step in addressing this issue by exploring the psychological and functional factors that affect transgender and non-binary youth with autonomic dysfunction. This research will serve as a foundation for future studies comparing the experiences of gender-diverse and cisgender youth.
Methods
Patients and Methods
This study retrospectively analyzed psychological and functional assessment data collected from adolescents under the age of 19 diagnosed with POTS, OI, or autonomic dysfunction/dysautonomia based on ICD-10-CM codes (G90.A, G90, and G90.9) between May 2022 and May 2024. In the ICD-10-CM classification, the code for POTS and OI is G90.A. Autonomic dysfunction or dysautonomia, is classified under the broader code G90, while G90.9 denotes an unspecified autonomic nervous system disorder. Participants were evaluated at the Center for Autonomic Research and Education (CARE) Clinic at Primary Children’s Hospital, a multidisciplinary clinic focusing on chronic pain, fatigue, and autonomic dysfunction. At our institution, we define OI and POTS based on the results of the Active Stand Test, which is performed on all patients. If the orthostatic vital signs (OVS) show a heart rate increase of less than 40 beats per minute but greater than 25 beats per minute, the patient is classified as having OI. If the increase in heart rate is greater than 40 beats per minute, the patient is classified as having POTS. Autonomic dysfunction, or dysautonomia, is used as a broader term for patients who either cannot complete the Active Stand Test or present with symptoms such as dizziness, fatigue, gastrointestinal dysfunction, headaches, and cognitive difficulties, where the heart rate increase is less than 25 beats per minute, and the symptoms are not specifically orthostatic or posture related. Symptoms had to be persistent for at least over 3 months to meet inclusion criteria. Patients with orthostatic hypotension (drop in systolic blood pressure of over 20 mm Hg or drop in diastolic blood pressure of over 10 mm Hg) were excluded from the study.
Approval for the study was obtained from the Institutional Review Boards at the University of Utah and Primary Children’s Hospital.
The primary independent variable of interest was gender identity, focusing specifically on individuals identified as non-binary and transgender. The “non-binary cohort” included participants identifying as non-binary or “other.” The “transgender cohort” included transgender males (FTM) and transgender females (MTF).
Anxiety symptoms were evaluated using the Generalized Anxiety Disorder-7 (GAD-7)26, a validated tool comprising seven items rated on a scale from 0 (not at all) to 3 (nearly every day). Scores ranged from 0 to 21, with cut-offs of 5, 10, and 15 indicating mild, moderate, and severe anxiety, respectively. The GAD-7 has demonstrated high sensitivity and specificity (≥0.8) in detecting anxiety disorders and is widely used across clinical populations.
Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), a 9-item measure that identifies symptoms of depression. Each item is scored from 0 (not at all) to 3 (nearly every day), yielding a total score between 0 and 27. Scores of 5, 10, 15, and 20 indicate mild, moderate, moderately severe, and severe depression, respectively27. The PHQ-9 also includes an item assessing the impact of depressive symptoms on daily functioning. Major depression is diagnosed if 5 or more symptoms, including depressed mood or anhedonia, persist for more than half the days in the past 2 weeks.
Functional disability was measured using the Functional Disability Inventory (FDI), a 15-item self-report tool that evaluates illness-related limitations in daily activities, such as school attendance and social participation. Scores range from 0 to 60, with higher scores indicating greater disability. FDI scores are categorized into no/minimal disability (0–12), moderate disability (13–29), and severe disability (≥30)28,29. The FDI is validated in populations with chronic pain and autonomic dysfunction, making it a robust measure of functional impairment in this study.
Somatic symptom burden was assessed using the Somatic Symptom Scale-8 (SSS-8)30, a brief measure that evaluates the severity of 8 common physical symptoms: stomach or bowel problems, back pain, headaches, chest pain, dizziness, fatigue, trouble sleeping, and shortness of breath. Each symptom is scored from 0 (not at all) to 4 (very much), with a total score ranging from 0 to 32. Scores of 4, 8, 12, and 16 represent mild, moderate, severe, and very severe symptom burden, respectively. The SSS-8 is well-suited for populations with chronic and unexplained medical conditions and provides insight into the physical symptom burden experienced by participants.
Pain catastrophizing, which reflects maladaptive cognitive and emotional responses to pain, was measured using the Pain Catastrophizing Scale-Child Version (PCS-C)31–33. The PCS-C includes 13 items assessing 3 dimensions: rumination, magnification, and helplessness. Each item is rated from 0 (not at all) to 4 (all the time), with total scores ranging from 0 to 52. Higher scores indicate greater catastrophizing, which is associated with higher pain intensity and disability. The PCS-C has been validated in pediatric populations with chronic pain and autonomic dysfunction.
Participants completed all self-reported assessments electronically through REDCap as part of the clinic’s admission process. Study data were collected and managed using REDCap electronic data capture tools hosted at Intermountain Health (Primary Children’s Hospital)34,35. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources.
Data Analysis
Descriptive statistics were used to summarize the psychological and functional scores of the participants, including mean scores and standard deviations for each psychological and functional assessment measure.
For comparative analyses, participants were categorized into 2 groups based on gender identity. Chi-square tests were conducted to examine differences between the 2 groups, focusing on psychological and functional outcomes. This allowed for the identification of statistically significant associations between gender identity and reported measures of anxiety, depression, functional disability, somatic symptoms, and pain catastrophizing.
All statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC), and a significance threshold of P < .05 was applied.
Results
The study included 23 participants with a mean age of 17 years (range 10–19). The non-binary cohort consisted of 13 individuals, including 12 identifying as non-binary and 1 classified as “other.” The mean age of this cohort was 17 years. The transgender cohort included 10 participants, comprising 9 transgender males and 1 transgender female, with a mean age of 17 years. These groups provided the foundation for examining psychological and functional outcomes related to gender identity among adolescents with autonomic dysfunction (Table 1).
Table 1: Characteristics and Key Measures for Each Cohort
| Characteristic | Non-Binary Cohort (n = 13) | Transgender Cohort (n = 10) | Total (n = 23) |
| Mean Age (years) | 17 | 17 | 17 |
| Age Range (years) | 10-19 | 10-19 | 10-19 |
| Number of Participants | 13 | 10 | 23 |
| Non-Binary Participants | 12 | – | 12 |
| “Other” Gender Participants | 1 | – | 1 |
| Transgender Male Participants | – | 9 | 9 |
| Transgender Female Participants | – | 1 | 1 |
No statistically significant differences were observed between the 2 cohorts. The mean depression score was 9.3 in the transgender cohort and 7.8 in the non-binary cohort. The mean anxiety score was 11.2 in the transgender cohort and 9.9 in the non-binary cohort. Pain catastrophizing scores were 21.2 in the transgender cohort and 20.9 in the non-binary cohort.
In terms of somatic symptom burden and functional disability, the non-binary cohort had higher mean scores. The mean SSS-8 score was 16.5 for the non-binary cohort and 14.7 for the transgender cohort. The mean FDI score was 25.8 in the non-binary cohort and 20.7 in the transgender cohort. See Table 2 for detailed information on cohort characteristics and scores.
Table 2: Comparing Psychological and Functional Scores Between Non-Binary vs. Transgender Cohort.
| Outcome Measure | Non-Binary Cohort (n = 13) | Transgender Cohort (n = 10) | P-value |
| Depression (PHQ-9) | 7.8 (SD 4.7) | 9.3 (SD 3.2) | 0.37 |
| Anxiety (GAD-7) | 9.9 (SD 6.5) | 11.2 (SD 4.3) | 0.46 |
| Somatic Symptom Burden (SSS-8) | 16.5 (SD 6.0) | 14.7 (SD 4.8) | 0.44 |
| Functional Disability (FDI) | 25.8 (SD 10.0) | 20.7 (SD 7.7) | 0.24 |
| Pain Catastrophizing Scale (PCS-C) | 20.9 (SD 12.9) | 21.2 (SD 12.5) | 0.73 |
Discussion
This is the first study to examine psychological factors and functional disability in gender-diverse youth with autonomic dysfunction. Although no significant differences were observed between non-binary and transgender individuals, the findings suggest that both groups experience heightened psychological distress, particularly in areas such as anxiety and pain catastrophizing. Compared to transgender individuals, non-binary youth demonstrated slightly higher scores on measures of somatic symptom burden and functional disability. However, these differences did not reach statistical significance, indicating that both groups may experience similar challenges in terms of psychological and functional outcomes. This study contributes to the growing body of literature on gender-diverse youth with chronic illness, particularly those with autonomic dysfunction.
Mayo conducted a study examining subjectively experienced cognitive difficulties in cisgender youth with POTS, exploring the pathophysiology and psychological contributions to these cognitive impairments36. The study assessed various factors, including pain catastrophizing and functional disability. The Pain Catastrophizing Scale for Children (PCS-C) in their study yielded a mean score of 23 (SD = 11), with scores ranging from 0 to 52. In our study, the transgender cohort had a mean PCS-C score of 21.2, and the non-binary cohort had a mean of 20.9. For functional disability (FDI), Mayo reported a mean score of 27 (SD = 11), with scores ranging from 2 to 52. Our study found a mean FDI score of 25.8 in the non-binary cohort and 20.7 in the transgender cohort.
While our study and Mayo’s study report on autonomic symptom severity and anxiety, a direct comparison could not be done due to the different scales used in each study. Mayo employed the COMPASS-31 to measure autonomic symptoms and the Spence Children’s Anxiety Scale (SCAS) and Multidimensional Anxiety Scale for Children (MASC) for anxiety, making comparing the results difficult.
Yet another study in adults37 with autonomic dysfunction reported mean scores for the PHQ-8 (11.8 ± 6.1), PHQ-15 (19.8 ± 4.8), GAD-7 (8.3 ± 6.4), and PCS (18.8 ± 12.5)37. Although adult data provide a useful context for interpreting these findings, the current study emphasizes the need for additional pediatric research to fully characterize the psychological and functional outcomes of adolescents with autonomic dysfunction. Age differences between our study group and the larger published studies limit direct comparisons.
Clinical Implications
The findings demonstrate that gender-diverse youth with autonomic dysfunction may experience psychological challenges such as anxiety, depression, pain catastrophizing, and significant functional disability. A multidisciplinary approach, including psychological screening and tailored interventions, is crucial for addressing their needs. However, a cisgender comparison cohort is needed to better understand how gender identity influences the psychosocial and functional aspects of autonomic dysfunction, enabling healthcare systems to more effectively support gender-diverse youth.
Limitations
Although this study has several strengths, including being the first to explore psychological and functional patterns in gender-diverse adolescents with autonomic dysfunction, several limitations impact the results.
Firstly, the small sample size restricts the ability to generalize the findings to the broader population of gender-diverse adolescents with autonomic dysfunction. With only 23 participants, the study may not fully capture the range of experiences and outcomes seen in a larger, more diverse cohort. This limitation underscores the need for future studies with larger sample sizes to enhance the generalizability and reliability of the findings. Also, the study did not include cisgender groups with and without autonomic dysfunction, which would have been valuable for comparing the psychological and functional outcomes between gender-diverse and cisgender adolescents with and without autonomic dysfunction. Without a cisgender cohort, there is no clear baseline to determine whether the observed patterns are unique to gender-diverse adolescents or are part of a broader trend in youth with autonomic dysfunction. Including cisgender adolescents as a control group in future studies will be essential for contextualizing the findings and better understanding the role of gender identity in the experience of autonomic dysfunction.
Secondly, the absence of parental scoring or perspectives is another important limitation. Parental reports would provide additional insight into the adolescent’s condition, particularly how it affects family dynamics and the overall impact on daily life. By not including parental input, the study misses a critical component that could offer a more comprehensive understanding of the challenges faced by gender-diverse youth with autonomic dysfunction. Future research should aim to incorporate both adolescent and parental perspectives for a more holistic view of the condition’s impact.
Thirdly, the participants in this study visited a multidisciplinary clinic, which likely represents a subset of adolescents with autonomic dysfunction with more significant functional disability and severe manifestations of the condition, meaning the findings may not reflect the experiences of those with less severe autonomic dysfunction. This limits the generalizability of the findings to adolescents with milder symptoms or those seen in primary care settings. Future research should include a broader sample from various clinical settings, including primary care, to capture a wider range of symptom severity and functional impairment.
Fourthly, the cross-sectional design of the study limits the ability to determine the directionality of the relationships between the variables measured. Although functional disability was treated as a dependent variable, it is possible that functional disability contributes to poorer psychological outcomes rather than the reverse. The study provides valuable information about associations between these factors, but it does not establish causality. Longitudinal studies are needed to better understand the causal relationships between psychological and functional outcomes and how these relationships may change over time in adolescents with autonomic dysfunction.
Finally, in this study, we were unable to distinguish between OI, POTS, and autonomic dysfunction/dysautonomia diagnoses. This limitation occurred because the data in REDCap were not separated by diagnosis, as all patients were grouped under the same project. As a result, we could not distinguish between OI, POTS, or autonomic dysfunction for the purposes of this study. This should be considered when interpreting the results.
Future Directions
Gender-diverse youth with autonomic dysfunction may experience psychological challenges, including anxiety, depression, pain catastrophizing, and significant functional disability. Future studies should expand to include cisgender youth with autonomic dysfunction to enable meaningful comparisons and provide insights into how gender identity influences psychological and functional outcomes. This understanding will help develop more personalized and effective care strategies for gender-diverse adolescents.
Longitudinal studies are needed to examine the psychological and functional trajectories of gender-diverse youth over time, focusing on symptom progression, treatment regimens, and quality of life. Further research should explore the effects of medications, particularly hormonal therapies, on autonomic function, mood, and daily functioning. Additionally, broader hormonal and social factors, such as gender-affirming hormone therapy, social support, and societal acceptance, should be examined to understand their role in symptom expression and outcomes. A comprehensive model that incorporates psychological and functional health factors for both cisgender and gender-diverse patients is necessary to address the needs of all adolescents with autonomic dysfunction and promote more inclusive care.
Acknowledgments
I would like to extend my sincere gratitude to the nurses, counselors, occupational therapists, physical therapists, dieticians, and all other healthcare providers who deliver exceptional care to the patients featured in this study. I also want to thank the individuals with POTS, OI, and autonomic dysfunction for their strength and determination, and for allowing us the privilege of being a part of their journey.
Affiliations
Kirti Sivakoti, MD¹, Corinne Espinoza, PhD¹, Deirdre Caplin, PhD¹, Stanley Brewer, DO¹, Shauna L. Skog, NP2, Judith S. Sampson, NP2, Philip Fischer, MD3, Casey Tak, PhD, MPH⁴
Affiliations: University of Utah, Department of Pediatrics¹, Intermountain Health2, Mayo Clinic, General Pediatrics and Adolescent Medicine Division3, and University of Utah, College of Pharmacy4
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical Approval
The Institutional Review Board of Primary Children’s Hospital and University of Utah both approved study procedures and waiver of consent.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
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