Kallmann syndrome (KS) is a congenital hypogonadism due to hypothalamic gonadotropin-releasing hormone disorders, accompanied by anosmia, accounting for about 60% of idiopathic hypogonadotropic hypogonadism
[1-2]. Its prevalence ranges from 1/10 000 to 1/60 000, with 5 times higher in men
[3]. Besides puberty delay and body deformities, KS patients may have psychosocial impairment, especially anxiety and depression. There is limited literature on depression incidence in KS patients, and most patients experience body shame
[4-5]. Anxiety and depression often co-exist and can persistently impair psychosocial functioning and physical health, increasing the disease burden
[6]. Thus, identifying potential factors associated with anxiety and depression in KS patients can enhance our understanding of the disorder and help devise strategies to improve patients’ quality of life.
Previous study
[7] showed that in KS patients, abnormal pubertal development, distorted body image and delayed diagnosis are linked to psychological issues like impaired self-esteem, shame, loneliness, and self-stigma. These psychological changes may be associated with anxiety and depression. Stigma has three components: stereotyping, prejudice and discrimination
[8]. In KS patients, self-stigma, due to perceived “difference” or “defectiveness” from symptoms and internalized societal biases, is associated with shame about gender identity and body image. Prior research
[9] suggested a positive correlation between self-stigma with shame and anxiety and depression, which was validated in people with physical disabilities
[10]. However, the psychological mechanisms linking self-stigma to anxiety and depression in KS patients are poorly understood and need further empirical investigation.
A substantial body of literature
[11-13] has established reciprocal relationships among insomnia, anxiety, and depression. According to the cognitive model of insomnia, self-stigma, through its induction of ruminative thinking and cognitive arousal, constitutes a pivotal mechanism in insomnia’s development
[14-16]. We therefore hypothesize that insomnia functions as a critical mediator linking self-stigma to emotional dysregulation, disrupting both neurophysiological processes and daytime functioning. Specifically, we propose a directional pathway whereby self-stigma contributes to insomnia, which subsequently amplifies symptoms of anxiety and depression. In this model, sleep disturbance represents the physiological and cognitive mechanism through which psychological stress is transduced into clinically significant emotional symptomatology.
Self-stigma in KS patients is associated with impulsivity, emotional dysregulation, and maladaptive coping behaviors, wherein shame function as the core mechanism
[17]. Moreover, insomnia may mediate the relationship between self-stigma and heightened anxiety/depressive symptoms, constituting both a mechanistic pathway and a manifestation of psychological distress. Longitudinal studies
[15, 18] confirm that insomnia serves as a prodromal symptom of affective disorders and a critical bridge between psychosocial stress and emotional dysfunction. These interrelated factors establish a self-perpetuating cycle: Self-stigma engenders impulsivity and emotional dysregulation, promotes maladaptive coping strategies, and precipitates insomnia that impairs daily functioning and amplifies affective symptoms. This exacerbation of emotional problems subsequently reinforces self-stigma, completing a feedback loop that compromises recovery. Elucidating these reciprocal mechanisms is essential for developing targeted interventions to disrupt this cycle and enhance clinical outcomes.
Building upon this theoretical framework, this study tests an underexplored pathway wherein self-stigma and impulsivity contribute to insomnia, which in turn mediates the severity of anxiety and depressive symptoms in KS. Using a cross-sectional design, we propose 2 core hypotheses. Firstly, individuals with KS will exhibit elevated rates of self-stigma, impulsivity, insomnia, anxiety, and depression. Secondly, insomnia will function as a mechanistic intermediary between self-stigma/impulsivity and affective dysfunction. The novelty of this investigation lies in its systematical evaluation of an integrated psychopathological model within the KS population. By delineating these reciprocal mechanisms, this study aims to identify specific targets for psychological interventions and thereby enhance long-term clinical outcomes.
1 Participants and methods
1.1 Ethical statement
The study was approved by the Clinical Medical Ethics Committee of Xiangya Hospital of Central South University (2022101052), and written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.
1.2 Participants
KS patients were recruited from multiple medical centers across China, including Xiangya Hospital of Central South University and Henan Provincial People’s Hospital, and all completed psychological questionnaires at Xiangya Hospital. The nationwide geographical distribution of these patients is presented in the Sankey diagram (
Figure 1A). This study enrolled patients who met the clinical diagnostic criteria for KS
[1]. All eligible patients were required to present both core features: 1) Congenital hypogonadotropic hypogonadism, manifested as delayed or absent puberty, with serum levels of gonadotropins (luteinizing hormone, follicle-stimulating hormone) and sex hormones (testosterone/estradiol) falling within the prepubertal or low range; 2) congenital olfactory dysfunction (hyposmia or anosmia), objectively confirmed by olfactory testing. Furthermore, secondary causes such as pituitary adenomas, other hypothalamic-pituitary structural lesions, and head trauma were ruled out through radiographic imaging. The study enrollment process was presented in
Figure 1B.
1.3 Instruments
1.3.1 General situation questionnaire
The participants’ socio-demographic data, including age, gender, height, weight, body mass index (BMI), and educational attainment, were recorded.
1.3.2 Self-stigma Scale-Short Form
Self-Stigma Scale-Short Form (SSS-S) was used to assess self-stigma. We used the 8-item concise version scored on a Likert scale from 1 (strongly disagree) to 5 (strongly agree). Higher SSS-S aggregate scores meant more pronounced self-stigma. The Cronbach’s α coefficient was 0.95, showing high reliability
[19].
1.3.3 8-Item Athens Insomnia Scale
8-Item Athens Insomnia Scale (AIS-8) was used to assess past-month subjective insomnia severity. Based on the requirement of each main complaint occurring at least 3 times last month, a 4-level scoring method (0 to 3 points per item) was used. Higher scores indicated worse sleep quality. The Cronbach’s α coefficient was about 0.88
[20].
1.3.4 8-Item Barratt Impulsiveness Scale
8-Item Barratt Impulsiveness Scale (BIS-8) was used to assess individuals’ impulsivity. It had 8 items like poor self-control and impulsive behavior. The scale used Likert 4-level score, and items 1, 4, 5, and 6 were reverse scoring questions. A higher score indicated more impulsivity. The Cronbach’s α coefficient was 0.85
[21].
1.3.5 2-item Generalized Anxiety Disorder
2-Item Generalized Anxiety Disorder (GAD-2) was used as a screening instrument for generalized anxiety disorder. It had 2 questions about generalized anxiety symptoms, focusing on an individual’s anxiety experience and frequency in the past 2 weeks. Each question employed a 4-point Likert scale ranging from 0 to 3. A cut-off ≥2 on the GAD-2 is established as a highly sensitive screen for anxiety
[22], and we screened for GAD using a 3-point cut-off. The Cronbach’s α coefficient was 0.806
[23].
1.3.6 2-Item Patient Health Questionnaire
2-Item Patient Health Questionnaire (PHQ-2) was used to assess depressive symptoms over the past 2 weeks, including depressive mood and anhedonia. The score of each item ranged from 0 to 3, and the PHQ-2 score ranged from 0 to 6. Evidence supports a PHQ-2 cutoff ≥2 to optimize sensitivity and specificity
[24]. We selected 3 as the entry point, considering scores >3 as indicating depression. The Cronbach’s α coefficient was about 0.71
[25].
1.3.7 De Jong Gierveld Loneliness Scale
De Jong Gierveld Loneliness Scale (DJGLS) was employed in its 6-item short-form version to measure loneliness. This scale evenly divided its items between 2 dimensions: Emotional and social loneliness. Responses were scored on a 5-point Likert scale, ranging from 1 (strongly disagree) to 5 (strongly agree). Higher scores meant more loneliness. The Cronbach’s α coefficient was 0.76
[26].
1.4 Measures
Participants were classified as having clinically significant anxiety if their GAD‑2 score was ≥3, and clinically significant depression if their PHQ‑2 score was ≥3. The comorbidity indicator Ci for each participant i was then derived using the following formula:
Ci =(GAD-2 i ≥3)+(PHQ-2 i ≥3).
Where (.) is the indicator function, which equals 1 if the condition in parentheses is true and 0 otherwise. Therefore, Ci =2 indicating the presence of both anxiety and depression.
1.5 Statistical analysis
All analyses were conducted in Jamovi (version 2.5.4.0) and SPSS (version 27.0; IBM Corp., Armonk, NY, USA). Graphs were generated using GraphPad Prism (version 10.1.2). Statistical significance was defined as
P<0.05 (two-tailed). Descriptive statistics are expressed as mean and standard deviation. Handle missing data using listwise deletion. Normality was evaluated via the Shapiro-Wilk test, given that BIS, AIS, SSS, and DJGLS exhibited minor deviations despite high
W-values, anxiety-depression composite scores demonstrated significant skewness, non-parametric methods were employed conservatively for intra-group comparisons (Supplementary Figure,
https://doi.org/10. 57760/sciencedb.35404). Logistic regression analysis was used to identify factors associated with clinically significant anxiety and depression. Subsequently, a serial multiple mediation model was specified with self-stigma as the independent variable, anxiety-depression composite score as the dependent variable, and impulsivity and insomnia as sequential mediators. The model was estimated in Jamovi using the medmod module with bias-corrected bootstrap confidence intervals (5 000 resamples). Indirect effects were considered significant if the 95% confidence interval (
CI) excluded zero. Age, gender, and education were included as covariates.
2 Results
2.1 Associated factors for anxiety and depression
The total anxiety and depression score was used as the dependent variable and the scores of each psychological scale (SSS-S, AIS-8, BIS-8, DJGLS) as the independent variables to predict possible associated factors for anxiety and depression in KS patients. Age, gender, and education were used as covariates. Univariate Logistic regression analyses revealed associated factors for anxiety-depression including self-stigma (SSS-S,
OR=1.189,
P<0.001), impulsivity (BIS-8,
OR=1.104,
P=0.005), insomnia (AIS-8,
OR=1.167,
P<0.001), and loneliness (DJGLS,
OR=1.372,
P<0.001) (
Figure 2). Further multivariate Logistic regression analyses were performed for variables with statistically significant results from univariate analysis (
Figure 3), and the results showed that self-stigma (SSS-S,
OR=1.112,
P=0.003), insomnia (AIS-8,
OR=1.098,
P=0.017), and loneliness (DJGLS,
OR=1.198,
P=0.007) were independent associated factors for anxiety and depression in KS patients.
2.2 Sequential multiple mediation analysis
As shown in
Table 1, the serial mediation model revealed three significant indirect pathways (all bias-corrected 95%
CIs excluded zero). The direct effect of self-stigma on anxiety/depressive symptoms remained significant after accounting for mediators (c’=0.147,
P<0.001, 95%
CI 0.091 to 0.201), suggesting partial mediation. The specific indirect pathway through both impulsivity and insomnia was significant (indirect effect 3=0.013,
P=0.008, 95%
CI 0.004 to 0.024).
3 Discussion
This study confirms a high burden of anxiety and depression in individuals with KS and identifies a cluster of interrelated contributing factors. In addition to confirming known associations between self-stigma and loneliness, we identified a high prevalence of clinically significant insomnia—a novel finding in this KS population. Mediation analysis revealed that self-stigma’s impact on emotional distress is partially transmitted through 2 distinct mechanisms: Behavioral dysregulation (impulsivity) and sleep disruption (insomnia). By delineating these specific mediators, our study refines theoretical models of psychopathology in KS and provides empirically grounded targets for intervention.
Our analyses identified loneliness as an independent predictor of anxiety and depression symptoms in KS patients, a finding consistent with prior research
[4, 7] documenting elevated rates of social isolation in this population. Longitudinal investigations have further demonstrated that many patients experience public teasing and body-related shame
[27], experiences that erode self-esteem. Our results suggest loneliness amplifies these feelings, thereby creating a reciprocal cycle of vulnerability. These findings underscore the need for future intervention research examining whether targeted social support programs can attenuate loneliness and improve psychosocial outcomes.
This study documented significant self-stigma among patients with KS, which was associated with heightened anxiety and depressive symptoms. Diagnostic delay is common due to the condition’s rarity and can independently worsen mental health outcomes while reinforcing self-stigmatizing beliefs
[28-29]. Beyond core features of infertility and hypogonadism, these patients frequently present with comorbid conditions, including congenital hearing deficits, renal anomalies, skeletal malformations, and ophthalmologic defects
[30]. That may compromise physical appearance and functional capacity. Moreover, the somatic manifestations of androgen deficiency, such as altered body composition, gynecomastia, and incomplete development of secondary sexual characteristics
[31], likely amplify body-related shame and contribute to internalized stigma.
A key novel finding is the high prevalence of insomnia in KS—a factor that remains understudied in this population. Insomnia is not merely a symptom but a potential mechanistic factor
[32]. Its established bidirectional relationship with mood disorders suggests a vicious cycle may be operative in KS: Emotional distress disrupts sleep, and the resulting sleep fragmentation exacerbates negative affect and impairs emotional regulation. This study identifies as both a significant predictor of anxiety/depression and a critical mediator linking self-stigma to affective symptoms. Together with impulsivity, which emerged as an additional behavioral mediator, these findings delineate distinct pathways through which self-stigma contributes to emotional distress in KS.
While impulsivity is established as an independent risk factor for affective disorders in the general population
[33], our findings demonstrate a more circumscribed role in KS: Impulsivity did not emerge as a direct predictor of anxiety/depression. This pattern reflects 2 considerations. Firstly, our cross-sectional design precludes establishing temporal precedence, necessitating longitudinal research to determine causal ordering. Secondly, in KS, impulsivity may be downstream from self-stigma, a behavioral manifestation of internalized stigma rather than a primary etiological agent. Our mediation framework captures this indirect pathway, positioning impulsivity as a mechanism through which self-stigma exerts its effects, rather than an independent risk factor.
This study underscores the importance of addressing the mental health needs of KS patients. Potential interventions such as psychotherapy (e.g., cognitive behavioral therapy)
[34] and physiotherapy (e.g., repetitive transcranial magnetic stimulation)
[35] may help with the patients’ psychosocial impairment. Additionally, strategies designed to reduce impulsivity should also be helpful to increase the quality of life of the KS patients
[36]. Lastly, pharmacological and behavioral interventions for improving sleep quality should also be beneficial for the patients’ well-being
[37].
Several limitations warrant consideration. Firstly, our sample comprised only Chinese patients, limiting generalizability to other populations. Secondly, the rarity of KS constrained our sample size, precluding stratified analyses and examination of additional covariates (e.g., medication use, socioeconomic status, and disease duration). Thirdly, the cross-sectional design precludes assessment of temporal relationships and causal inference. Future research should employ large-scale, longitudinal, and multinational designs to validate this model. Such studies are particularly needed to evaluate long-term mental health trajectories following targeted psychosocial and behavioral interventions.
Contributions: TANG Xiong, WU Feifei Research design, paper writing and revision; WU Han Data collecting, analysis, and correction; HE Yafang, ZHANG Jinfan, and HUANG Haimiao Data collecting and analysis; MEN Meichao, YI Xiaoping, and CHEN T. Bihong Research design, paper supervision and revision. The final version of the manuscript has been approved and read by all authors.
the Natural Science Foundation of Hunan Province(2023JJ30926)
the Fundamental Research Funds for the Central Universities of Central South University(1053320220341)
,
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