The main findings of this study were that women with TS in general had lower frequency of psychiatric diagnosis than those obtained from women of similar age in the general population-based register, and that there were no associations between psychiatric diagnosis and karyotypes in TS. The most common psychiatric diagnoses were mood and anxiety disorders, followed by disorders of adult personality and behavior. The frequency of depression diagnosis during more than two decades was less than 10%. Apart from the fact that depression is more common in women in general, they are also diagnosed with more comorbidities than men (15, 26). The life-time risk of developing depression for women at some point in life is 36% in Sweden. (27). Although higher lifetime prevalence rate of depression was found for the whole group of women with TS, the frequency of depression diagnosis was 9.9%, which is far below the community rate (Table 3).
Both anxiety, and depression can occur as part of other psychiatric disease processes (28). Anxiety disorders are the most common diagnosis of mental disorders, affecting more often women with greater illness burden. (20, 17, 19–20). The conditions are often long-lasting, and the risk of relapse is high. (29). The reported prevalence of anxiety in Swedish female population varies between 11% (very severe anxiety) to 41% (moderate to mild form) (27). The prevalence of anxiety disorders in the study group of TS was considerably lower than the severe forms in the general population.
It is rational, and expected, that the comorbidity of a second psychiatric condition along with depression would be more common than co-occurrence of depression with TS due to the overlapping biochemical processes and predisposing life events related to psychiatric diseases. Thus, sex differences in psychiatric disorders may be a result of a complex interplay between genetic, hormonal, immunological, and psychosocial factors (30–32). Mortality rates among people treated for depression and anxiety disorders is 70% higher compared to the rest of the population, in Sweden. (27). This was, however, not seen for women with TS in the present assessment. During the observation period, one woman with TS without any psychiatric diagnosis committed suicide after an acute life crisis.
Neuroactive steroids seem to play a role in mood disorders (33–37). The gonads and adrenal cortex are the primary sources of testosterone in both sexes. Individuals with TS have a relative testosterone deficiency because of absence of ovaries. (38–39). Low testosterone levels in women with TS may be a risk factor for psychiatric illness, as testosterone supplementation has been shown to have anxiolytic and antidepressant effects in women (11). A randomized, double-blind, placebo-controlled crossover study has shown improved body composition, neurocognition, and quality of life in TS with androgen substitution. (40). Puberty was initiated, often along with androgens, in most girls with TS and around half of all had received growth hormone. Continuous estrogen hormone replacement was used by the majority but androgen substitution was not used in adults with TS in the present study.
An additional risk for depression for individuals with TS is fertility issues. The ovarian dysgenesis and hypergonadotropic hypogonadal state, results in infertility in the great majority of women with TS (41). It has been shown that, patients with infertility issues are more likely to suffer from a psychiatric illness than fertile patients (42–44). A nearly equivalent lifetime rate of a major depressive diagnosis was found in the women with TS as compared to women with ovarian insufficiency (55%), a condition with some shared hormonal and psychosocial factors (45). Nevertheless, the frequency of TS - women living with a child/children did not differ between those with psychiatric diagnoses compared to those without psychiatric diagnoses in this study.
Furthermore, autoimmune diseases seem to play a causative role in several neuropsychiatric disorders (1, 46–48), and generally more prevalent in individuals with chromosome aberrations than in the general population (46, 49) with variable prevalence in TS (50–51). The different features specific to TS place individuals at biologically greater risk for depression than individuals unaffected by TS. (52–53), and depression has also been observed in populations with shared characteristics, such as chronic medical conditions (35, 54–55).
However, in the present study no significant differences were found between women with TS and those with or without psychiatric diagnoses with respect to autoimmunity, aortic dissection, ischemic heart diseases, and chronic medical conditions.
Low quality of life has been stated as a risk factor for depression in TS. With respect to the health-related quality of life (HRQoL) studies, Krantz et al., (2019) reported similar HRQoL to the reference population in women with TS in a study from Sweden (56).
The systematically medical controls of individuals with TS diagnoses, from birth to senior years, according to Turner Academy recommendations since 1994, could possibly explain this result.
To our knowledge, there are no studies on alcohol use in women with TS. Kagan-Krieger et al., (2002), found no association between paternal or maternal alcohol consumption and TS. (57). In the present study, problems related to alcohol consumption were related to the presence of psychiatric disorders, as six individuals with TS, had received hospital care more than once due to alcohol intoxication, delirium tremens, and all had comorbid psychiatric disorders.
Difficulties with visual-spatial reasoning, visual-spatial memory, attention, executive functioning, and motor skills seem more common in girls with TS than the general population. (8, 53). An increased risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders in women with TS has been suggested. (6, 58). However, the frequency of ADHD and autism in the present study was not higher than in the general population.
The associations of TS with schizophrenia, and schizophrenic psychoses has been described in several case reports (2, 12, 14), and mosaic karyotype 45,X/46,XX was clearly overrepresented. (7, 59–60). Schizophrenia is a chronic, complex mental illness that seems to disrupt several cognitive functions and affects 0.4% of Swedish population (27, 61). There were only three women with TS who had a schizophrenia diagnosis in the present report but still more common than in the general population (Table 3). Two of these three women with TS had autism spectrum disorders. Furthermore, publications about TS and eating disorders, especially anorexia nervosa, is extremely rare though there are case reports (62–64). In the present study only two women had anorexia nervosa, (Table 3).
The phenotype seen in TS seems to depend on gene dosage due to X chromosome monosomy, but also on a complex relationship between genes as well as transcriptional and epigenetic factors affecting gene expression across the genome. (39).
Although advances in research, and the medical care of women with TS, several studies, a few with control subjects included, have shown a higher prevalence of depressive symptoms (43, 65). Existing data show that the diagnostic method of assessing depression has been different in different studies, and this may create difficulties to compare the studies. Nevertheless, the Consortium on the Management of Disorders of Sex Development, suggests that women with TS should be regularly screened for depression in the general medical setting like other medically ill groups (1, 4, 54). Kremen et al., (2023) also points out that existing screening and referral patterns for neuropsychological and mental health matters should be well characterized, and prevalence of and risk factors should be described in a standardized manner (66).
In the clinical settings the younger generation of women with TS point out lack of psychological support. Even though there are numerous potential risk factors for depression related to the biological and psychosocial characteristics of TS, higher rate of social skills difficulties than age-matched girls from the general population (6) or increased frequency of depression could not be confirmed in this study. Psychiatric disorders may be a result of a complex interplay between genetic, hormonal, immunological, and psychosocial factors, but having TS does not necessarily imply more morbidity in mental illnesses. However, studies on mental health issues among women with TS are scarce. The vast majority of women with TS has normal intelligence, social functioning and has employment, yet there are case reports of psychiatric disorders in this syndrome. Given the frequency of TS, and the existing data, these questions warrant more scientific investigation to find evidence if the chromosomal abnormalities lead more often to psychiatric illness. If so, it is important to identify it to avoid labeling women with a more severe diagnosis and having optimal treatment strategies.
The strength of the study is the long-term follow up with clinical examinations of all women with TS during up to 25 years in Sweden. Medical records along with other clinical characteristics of all participants and data from national registries both in-patience and primary care settings, with nationwide coverage were studied. All listed diagnostic codes are consistent since the reporting to the National Board of Health and Welfare's health data register is compulsory and regulated by law. Health care is publicly funded with universal access to both primary care and non-primary care in Sweden (67). Another strength is the knowledge of exact karyotypes for all participants in the study. Women with TS and psychiatric diseases could also be compared with their peers without any psychiatric conditions regarding medical history and anthropometry.
Limitations, even though almost nationwide coverage, a small number of women with TS did not want to participate in research projects. There was also lack of data on family history of psychiatric diseases in those individuals with TS, who had mood and/or psychiatric disorders.