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Emotional state, cognitive functioning and quality of life of adult women with Turner syndrome in Lithuania
Growth Hormone & IGF Research 45 (2019) 37–42
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Emotional state, cognitive functioning and quality of life of adult women with Turner syndrome in Lithuania
T
Lašaitė L.a, , Krikščiūnienė R.b, Žilaitienė B.a, Verkauskienė R.a ⁎
a b
Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania Lithuanian University of Health Sciences, Kaunas, Lithuania
ARTICLE INFO
ABSTRACT
Keywords: Turner syndrome Adult patients Emotional state Cognitive functioning Quality of life
Aim: The aim was to analyze emotional state, cognitive functioning and quality of life (QoL) of adult women with Turner syndrome (TS) in Lithuania. Patients and methods: Of all invited adult TS patients from Lithuanian TS database (n = 150), 68 (age 18–60, average 30.2 ± 9.0 years) agreed and were recruited for the study, as well as 68 age-matched healthy control women. Emotional state was evaluated by Profile of Mood States (POMS) questionnaire, cognitive functioning by Trail Making Test and Digit Span Test (DST) of Wechsler Adult Intelligence Scale, and QoL by WHO Brief Quality of Life Questionnaire (WHO QoL). Results: Patients with TS were of a significantly shorter stature (p < .001) than age-matched control women and than the 3rd percentile of the National Standards of Lithuania. After the adjustment for height, weight and body mass index (BMI), no significant differences in emotional state were detected, though without the adjustment, depression-dejection (p = .004) score was significantly higher in TS women than in age-matched controls. Significantly worse cognitive functioning (attention capacity, visual scanning abilities, executive function and psychomotor speed, p < .001), as well as worse psychological (p = .002) and social (p = .006) aspects of QoL were found after the adjustment for height, weight and BMI in adult women with TS than in age-matched controls. Conclusion: In conclusion, after the adjustment for height, weight and BMI, adult women with Turner syndrome in Lithuania have impaired cognitive functioning and worse psychological and social aspects of QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women.
1. Introduction Turner syndrome (TS) is a rare (affecting 25–50 per 100,000 females) genetic disorder that arises from a partial or complete loss of X chromosome material [1]. It is associated with a number of characteristic physical features (such as short stature, gonadal dysgenesis, lack of pubertal maturation, infertility, kidney and cardiac anomalies and others), as well as a particular social and behavioral features, a particular neurocognitive profile, deficits of memory, attention, social cognition and emotional recognitions [1,2]. In case of TS, it is common practice to treat short stature with growth hormone (GH) preparations and to induce puberty with estrogens at an age as close to normal puberty as possible in case TS girls do not go through spontaneous puberty [1]. But results of some studies show that even after reaching a height within the normal range and puberty induction at a pubertal age, some women with TS still
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experience psychosocial problems and lower QoL [3]. Many factors can affect their emotional state, cognitive functioning and QoL, such as increased marginalization by peers or self-marginalization, low selfesteem due to short stature or bullying, and other factors that might vary in different cultures. Usually adult women with TS not only experience a decreased health status, but also manifold psychosocial difficulties [4]. Some studies found normal QoL in young adult women with TS who reached normal height after GH therapy and had age-appropriate pubertal development [5]. On a large cohort study of women with TS treated by GH during childhood, Carel et al. [6] showed that their selfesteem and social adjustment were impacted by the comorbidities (such as hearing loss and heart diseases). In our previous study with a very small sample size, we found patients with TS in their adolescence and emerging adulthood after GH therapy discontinuation to have altered emotional state, impaired cognitive functioning and lower QoL than
Corresponding author. E-mail addresses: [email protected], [email protected] (L. Lašaitė).
https://doi.org/10.1016/j.ghir.2019.03.001 Received 31 August 2018; Received in revised form 22 February 2019; Accepted 17 March 2019 Available online 18 March 2019 1096-6374/ © 2019 Elsevier Ltd. All rights reserved.
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their healthy peers [7]. In older adult TS women no impairments in QoL were detected, except in the subscales of physical functioning, general health and social isolation [8]. Patients with TS usually show higher levels of alexitymia, more shyness, social anxiety, and lower self-esteem than those without TS. Also they score lower in tests on self-perception and attitude towards their body than normally developing girls, even after they achieve a height in the lower normal range with GH therapy [3,9]. Depression is rather prevalent psychiatric diagnosis in TS adults [10]. This psychological profile leads to a weaker social relationships and lower QoL [1,10]. Although their intelligence quotient (IQ) and verbal abilities are usually normal, some women with TS show impaired visual-spatial and spatial-numerical processing or disabilities affecting recognition or executive functions [11]. Deficits in executive functioning may include problems in switching attention between tasks, planning, inhibiting innapropriate responses and working memory (the transient holding, processing and manipulation of information) [11,12]. Reduced processing speed is also a frequent finding [12]. As a consequence of that, in addition to health-related problems, social interaction of TS women may be affected by difficulties in interpreting non-verbal communication, recognizing facial expression of certain emotions [13,14]. Human facial expressions are important social signals and provide a large variety of socially relevant information. So, face perception and emotion decoding are abilities of great importance in everyday life [15]. Impairments in social skills and affective discrimination characterize a substantial proportion of TS females, who possess limited numbers of friends and who experience social isolation as well as poor self-concept [16]. The aim of medical care and therapy should focus not only on the patient‘s physical health, but also on his psychosocial state and QoL. Data on different psychological aspects in patients with TS is still rather controversial. The aim of the study was to analyze emotional state, cognitive functioning and QoL in adult women with Turner syndrome in Lithuania.
A total of 68 age-matched healthy women were recruited for the control group of the study. They were randomly selected from those who arrived to the out-patient department and were found to have normal thyroid function and no other endocrine dysfunctions. Besides, no one of them had neither comorbid psychiatric disorders (such as major depressive disorder, dementia or anxiety disorder), nor any organic cerebral disorder, nor any chronic uncontroled/ untreated somatic disease at the period of the beginning of the study.
2. Subjects and methods
The Profile of Mood States (POMS) questionnaire was used for evaluation of emotional state of the participants [21]. It is a self-reported psychological measurement of immediate mood states. The POMS is a 65-item mood adjective checklist in which, using a five-point Likert-type scale, each adjective is scored from 0 (absent) to 4 (very much) based on how well each item describes the respondent's mood during the certain time frame (during the past week, including today). Following standard scoring methods, six mood scales are derived: tension-anxiety, depression-dejection, anger-hostility, vigour-activity, fatigue-inertia and confusion-bewilderment. A higher score denotes a higher level of certain emotion. Cognitive functions were assessed by Trail Making Test [22] and Digit Span Test (DST) of Wechsler Adult Intelligence Scale [23]. The Trail Making Test is a timed test in which the subject connects an altering sequence of numbers (Trail Making A) or numbers and letters (Trail Making B) in ascending order. The score on the Trail Making A test, which is based on time required to complete the sequence, is a measure of attention and visual scanning abilities, and Trail Making B is a test of executive function and psychomotor speed. A higher score denotes worse cognitive functioning. The Digit Span Test is a test in which the subject repeats sequences of numbers in a given order. The score of the test is a number or repeated number sequences in forward order and backward order. The test shows attention capacity and psychomotor speed. A higher score denotes better cognitive functioning. Generic WHO Brief Quality of Life Questionnaire (WHO QoL) questionnaire [24] was used for the QoL assessment. It consists of 26 questions and measures four subscales of quality of life: physical, psychological, social and environmental. A higher score represents better QoL.
2.2. Objective data The study was approved by Kaunas Regional Ethics Committee of Biomedical Research (No BE-2-32, 2014-06-03). All procedures were carried out with the adequate understanding and written consent of the subjects. The investigation was carried out in accordance with the Declaration of Helsinki. Anthropometrical measurements were made according to WHO guidelines [18]. Body mass index (BMI) was calculated as weight (kg)/ height (meters) squared [19]. Height and weight were compared to the National Standards of Lithuania [20]. Morning fasting vein blood samples of TS patients and of control women were taken. Serum was separated and stored at −20 °C until analyzed. Concentrations of insulin like growth factor −1 (IGF-1) (Biosource, Belgium), testosterone (Biosource, Belgium), thyroid stimulating hormone (TSH) (Immunotech, Czech Republic), free thyroxin (FT4) (Immunotech, Czech Republic) were measured by radioimmune assay. Luteinising hormone (LH) (Biosource, Belgium), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) (Immunotech, Czech Republic), estradiol (E2) (Immunotech, Czech Republic), dehidroepitestosterone - sulfate (DHEAS) (Immunotech, Czech Republic) were measured by immunoradiometric assay. 2.3. Psychological assessment
2.1. Subjects According to a Joint WHO/UNICEF Statement, the adult person is older than 18 years old [17]. Patients from the TS database of Lithuania who were older than 18 years at the time of the beginning of the study were invited to participate in the study. Of all invited 150 adult TS patients, 72 (48%) agreed to participate. Because of the previously diagnosed mental retardation, four women could not be recruited for the study. Other 78 (52%) invited TS patients did not respond (one of the possible explanations could be the high level of emigration from Lithuania). Patients with TS who did not respond were not researched, so it is not possible to know are there any differences in physical health, psychological state and QoL of the responders and non-responders. A total of 68 women diagnosed with genetically confirmed TS (66.2% 45, X0, and 33.8% non-45,X0, including mosaicism and izochromosome) were recruited for the study. Of all 68 TS women, 53 (77.9%) underwent GH therapy before (at least 6 months prior to the begining of the study). Their GH therapy lasted for at least one year until discontinuation after fusion of epiphyseal growth plates. The median duration of GH treatment was 3 years (25th – 75th percentile 1–6 years, average 3.26 years). Other 15 (22.1%) TS women did not recieve GH therapy because of the delayed diagnosing or sufficient adult height (n = 2, mean adult height 168 ± 0.8 cm). Also 34 (50.0%) of the researched patients were on natural estrogens, 18 (26.5%) were using oral combined contraceptive pills, and 16 (23.5%) were not receiving any sex hormone replacment therapy at the enrollement into the study. If required, all patients were on a stable and adequate adrenal and/or thyroid replacement. 38
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the mentioned significance disappeared after the adjustment for height, weight and BMI. So, no significant differences in emotional state were detected after the adjustment for height, weight and BMI. Both tests of cognitive functioning showed worse attention capacity, visual scanning abilities, executive function and psychomotor speed in patients with TS than in age-matched controls. The significance remained the same after the adjustment for height, weight and BMI (Table 3). Comparing QoL between women with TS and age-matched control women (Table 3), significant differences were detected in all subscales except environmental. Evaluations of physical, psychological and social subscales were significantly lower (meaning worse QoL) in adult women with TS than in control women. After the adjustment for height, weight and BMI, significance disappeared in physical scale. So, after the adjustment for height, weight and BMI, scores of psychological and social subscales were significantly lower (meaning worse QoL) in adult women with TS than in age-matched control women (Table 3). The group of the researched adult TS patients who were receiving sex hormone replacement therapy (n = 52), differed only in the environmental aspect of QoL (median 15.5 vs. 14.5, p = .020), but not in emotional state, cognitive functioning, other aspects of QoL (physical, psychological, social) from the TS patients who were not receiving any sex hormone replacement (n = 16). The group of the adult TS patients who did not undergo GH therapy before the beginning of the study (n = 15), were not significantly different in terms of emotional state, cognitive functioning, QoL from the TS patients who underwent GH therapy (n = 53). However, the stature of patients who recieved GH therapy was significantly higher when compared to untreated (median 152 cm vs. 148 cm, p = .016). No significant differences in terms of emotional state, cognitive functioning, QoL were found between the group of TS patients with 45, X0 (n = 45) and with non-45, X0 (n = 23) karyotypes. Significant correlations in adult women with TS were found between hormone concentrations and psychological state data (Table 4). FT4 concentration correlated negatively with emotional state (tensionanxiety, depression-dejection, fatigue-inertia, confusion-bewilderment), and positively with physical aspect of QoL. TSH concentration correlated positively with fatigue-inertia, and negatively with psychological aspect of QoL. Testosterone concentration correlated with psychological aspect of QoL, and negatively with cognitive functioning (attention capacity, visual scanning abilities, executive function and psychomotor speed). IGF − 1 concentration correlated positively with fatigue-inertia. DHEAS concentration correlated with cognitive functioning (attention capacity, visual scanning abilities). LH concentration correlated with cognitive functioning (attention capacity).
Table 1 The main anthropometric characteristics of adult women with Turner syndrome and age-matched control women. Categories
TS patients (n = 68), median (25th – 75th percentile)
Controls (n = 68), median (25th – 75th percentile)
p
Age, years, Height, cm, Weight, kg, Body mass index, kg/m2
29.0 (23.0–36.0) 151.7 (148.0–156.0) 56.0 (50.0–63.1) 23.9 (21.9–27.1)
29.0 (23.0–37.0) 168.0 (163.7–171.7) 61.0 (53.7–66.8) 21.8 (19.4–24.0)
0.807 < 0.001 0.023 < 0.001
2.4. Statistical analysis Analysis was performed using SPSS 23.0 software. The values are given as median and 25th–75th percentile. As the analyzed values were non-normally distributed, the differences between the means in groups were calculated using Mann-Whitney test as well as χ2 test. Adjustment for height, weight and BMI was performed by the Univariate Analysis of General Linear Model. Associations between somatic, hormonal and psychological data were determined using Spearman correlation coefficient. The limit of significance was defined as a two-sided p-value lower than 0.05. 3. Results Results of the main anthropometric characteristics of the study subjects with TS and age-matched controls are presented in Table 1, and their social characteristics in Table 2. Regarding the social state, less women with TS had university education, less were employed and more unemployed than the age-matched control women. Less women with TS were married or cohabiting and less of them had children (their own or adopted) than the control women. Patients with TS were of a significantly shorter stature than the control women (Table 1). The median height of TS patients was lower than the 3rd percentile of the National Standards of Lithuania (156.0 cm). The median height of age-matched control women was between the 50th and 75th percentile (163.0–171.0 cm) of the National Standards of Lithuania [20]. Weight of patients with TS was significantly lower and BMI was significantly higher than of the control women (Table 1). The median weight of adult women with TS was higher than the 10th percentile (51.0 kg) of the National Standards of Lithuania. The median weight of age-matched control women was slightly higher than the 50th percentile (60.0 kg) of the National Standards of Lithuania [20]. Regarding the emotional state (Table 3), depression-dejection was significantly higher in TS women than in control women, but no significant differences were found in tension-anxiety, anger-hostility, vigour-activity, fatigue-inertia and confusion-bewilderment. However,
4. Discussion The results of our study after the adjustment for height, weight and BMI revealed that adult women with TS in Lithuania have impaired cognitive functioning and worse psychological and social aspects of
Table 2 The main social characteristics of adult women with Turner syndrome and age-matched control women. Categories Education, n (%) Employment, n (%) Matrital status, n (%) Children, n (%)
Lower than university University Employed Studying Unemployed Single Married or cohabiting Divorced or separated or widowed Birth Adoption No children
TS patients (n = 68)
Controls (n = 68)
p
44 (64.7) 24 (35.3) 39 (57.3) 14 (20.6) 15 (22.1) 39 (57.3) 25 (36.8) 4 (5.9) 3 (4.4) 1 (1.5) 64 (94.1)
23 (33.8) 45 (66.2) 48 (70.5) 17 (25.0) 3 (4.5) 13 (19.2) 50 (73.5) 5 (7.3) 33 (48.4) 0 35 (51.6)
< 0.001 (χ2 = 21.5)
39
0.005 (χ2 = 10.7) < 0.001 (χ2 = 16.2) < 0.001 (χ2 = 32.2)
Growth Hormone & IGF Research 45 (2019) 37–42
L. Lašaitė, et al.
Table 3 Emotional state, cognitive functioning and quality of life in adult women with Turner syndrome, compared to age-matched control women. Categories
TS patients (n = 68), median (25–75 percentile)
Controls (n = 68), median (25–75 percentile)
P value
P value (adjusted for height, weight and BMI)
POMS, tension-anxiety⁎ POMS, depression-dejection⁎ POMS, anger-hostility⁎ POMS, vigour-activity⁎ POMS, fatigue-inertia⁎ POMS, confusion-bewilderment⁎ Trail Making A test ⁎⁎ Trail Making B test ⁎⁎ DDS forwards ⁎⁎* DDS backwards ⁎⁎* WHO QoL, physical ⁎⁎** WHO QoL, psychological ⁎⁎⁎* WHO QoL, social relations ⁎⁎⁎* WHO QoL, environmental ⁎⁎⁎⁎
4.5 (2.0–8.7) 6.5 (3.0–11.0) 6.5 (4.0–9.0) 17.0 (15.0–19.0) 5.0 (3.0–8.0) 2.0 (−0.7–4.0) 37.0 (31.0–54.2) 85.5 (67.7–101.7) 5.5 (4.0–7.0) 4.0 (4.0–5.0) 16.0 (14.8–16.6) 14.7 (13.5–15.3) 14.7 (13.3–16.0) 16.0 (15.0–16.5)
3.0 (1.0–7.0) 3.0 (2.0–7.7) 7.0 (4.0–9.7) 18.0 (16.0–21.0) 6.5 (4.0–9.7) 1.5 (−1.0–3.0) 26.0 (21.0–30.0) 53.0 (43.0–63.0) 7.0 (6.0–9.0) 7.0 (5.0–8.0) 16.6 (15.4–17.1) 15.3 (14.2–16.0) 16.0 (14.7–16.0) 16.0 (15.0–16.5)
0.232 0.004 0.339 0.084 0.118 0.337 < 0.001 < 0.001 < 0.001 < 0.001 0.014 0.001 < 0.001 0.957
0.248 0.141 0.675 0.145 0.516 0.245 < 0.001 < 0.001 < 0.001 < 0.001 0.077 0.002 0.006 0.449
A higher score denotes a higher level of certain emotion. A higher score denotes worse cognitive functioning. ⁎⁎⁎ A higher score denotes better cognitive functioning. ⁎⁎⁎⁎ A higher score denotes better quality of life. ⁎
⁎⁎
aspects of QoL, but not physical were worse in TS women compared to age-matched control women after the adjustment for height, weight and BMI (though if not adjusted, physical aspect of QoL was worse as well). Sutton et al. [27] suggested that short stature affects almost all TS women, either because they endured teasing over the years or were discouraged or frustrated by their dependence on other people to performe different tasks. TS patients show deficits in their emotional well-being as well as in their social functioning. Studies on the incidence of anxiety or depression in women with TS show conflicting data, possibly due to selection bias, disparate outcome measures and small sample sizes [28,29]. In general, women with TS experience lower self-concept compared to women without TS [28,30]. In our study we were not able to detect differences in emotional state between TS women and age-matched controls after the adjustment for height, weight and BMI, though without the adjustment depresion-dejection score was higher in TS women. Data is contradictory on QoL associations with vocational training and employment in TS women. Less employment or employment below the women's vocational training lead to lower overall life satisfaction correlated to professional life than in control women [31]. In contrast, some studies have reported educational achievements and job levels in women with TS equal [6] or even above that of the average female population [32]. In our study 22.1% of adult TS women reported to be unemployed, while in Lithuanian adult population unemployment level is 7.3% and in Lithuanian female population 5.7% [33]. Social functioning may also be hindered by specific cognitive profile in TS women with marked deficits in various visual-spatial and visualmotor skills, arithmetic abilities, executive functions and some language aspects, while other intellectual capacities are usualy preserved in TS [2,16,34]. Studies on psychomotor function suggest both general and specific motor impairments in TS, including dificulties in visualmotor coordination, learning and fine motor function [35]. In our study we found adult women with TS performing significantly worse in such aspects of cognitive functioning as attention, visual scaning abilities, executive function and psychomotor speed compared to age-matched control women. Several functional magnetic resonance imaging studies showed that TS women fail to incorporate frontal, executive functions related brain regions during performing visual tasks. Working memory difficulties in TS are related to differences in functional connectivity between parietal and frontal regions [36,37]. Neuroimaging studies in TS revealed abnormalities in several brain areas, known to be involved in emotional processing as well [38,39]. Lepage et al. [40] found that socio-emotional functioning in TS patients
Table 4 Significant correlations between hormone concentrations and psychological data in adult women with Turner syndrome. Significant correlations between POMS, fatigue-inertia POMS, fatigue-inertia WHO QoL psychological POMS, tension-anxiety POMS, depression-dejection POMS, fatigue-inertia POMS, confusion-bewilderment WHO QoL physical Trail Making A DDS forwards Trail Making A Trail Making B WHO QoL psychological
IGF - 1 concentration TSH concentration TSH concentration FT4 concentration FT4 concentration FT4 concentration FT4 concentration FT4 concentration DHEAS concentration LH concentration Testosterone concentration Testosterone concentration Testosterone concentration
r
p
0.298 0.263 - 0.280 - 0.293 - 0.303 - 0.390 - 0.288 0.257 −0.442 −0.327 −0.465 −0.426 0.260
0.032 0.039 0.026 0.020 0.016 0.002 0.022 0.042 0.006 0.009 0.003 0.006 0.045
QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women. The data presented are representative of adult women with TS in Lithuania, and it could be different if performed in other countries with different culture, religious views, social acceptance and support, different expectations and possibilities to adapt. We also found young adult women with TS to have lower height and weight and higher BMI than age-matched controls as well as the standard height and weight of the National Standards of Lithuania [20]. Usually untreated women with TS are approximately 20–21 cm shorter than healthy women within the respective population. Use of GH in usual doses increases growth in TS girls by approximately 3 cm in the first year of treatment and by approximately 2 cm per year after 2 years of treatment. Despite this increase, the final height of GH treated TS women usually is still outside the normal range [25]. In our study Lithuanian adult TS women had median height 151.7 cm, being approximately 11–12 cm less than 50th percentile (163.0 cm) of the National Standards of Lithuania [20]. Height gain from GH treatment in TS patients was found not to be associated with QoL scores, however, low QoL being related to the degree of short stature, although this can vary considerably and is dependent on the individual attitudes of patients [5]. Health-related QoL was shown to be worse in adult TS women than in general population and in age-matched control women in physical functioning domains, but not in psychological [26]. We did not find relation of height to any domain of QoL or emotional state. In our study psychological and social 40
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is related to their aberrant brain morphological structures. However, it is hard to determine whether the brain‘s unique morphological and activation patterns, observed in TS, are the cause of their social difficulties or the consequence of it. The brain serves as an endophenotype that bridges the gap between molecular genetics and complex behavior [41]. As demonstrated by genomic data, many X-linked genes are involved in postsynaptic protein coding, which is essential for neuronal plasticity and cognitive processes [42]. The X-linked genes have increased expression level in brain tissues, which supports an essential role of the X chromosome in brain development and mental functioning [43]. Relationships between specific brain phenotypes and behavioral-cognitive abilities may be altered in TS patients, and X chromosome loss may moderate brain relationships to behavior and cognition [39]. Approximately half of TS individuals exibit a complete loss of one X chromosome, termed X-monosomy (45, X0 karyotype), whereas approximately 10% of TS individuals exibit structural abnormalities in one of the two X chromosomes or more complex X chromosome abnormalities [44]. Physical and psychological features highly vary across women with TS as a result of the varied structural defects of the X chromosome or mosaicism [45]. In general, small deletions on the X chromosome or mosaicism likely manifest fewer and subtler TS features, whereas large deletions, or non-mosaicism karyotypes may result in the full spectrum of TS features. Most typical TS phenotypes are expected to occur in women who express a 45, X0 karyotype [45]. In our study we failed to detect psychological differences between TS patients with 45, X0 karyotype and with non-45, X0 karyotype, possibly because of a small sample size. Hormone deficiency might also impact brain regions involved in affect regulation and behavior [46]. Several studies have demonstrated significantly better visual-perceptual and visual-spatial abilities, motor planning skills in estrogen treated TS patients than in non-treated [2,47]. Ross et al. [48] suggested that these results reflect a specific influence of estrogen on brain maturation during puberty. More recent studies have demonstrated that brain morphometric changes during puberty are at least, in part, driven by estrogen [49,50]. But by adulthood, endogenous or exogenous estrogen has limited impact on modifying cognitive differences that likely arise much earlier in development [51]. Slightly better performance in psychological functioning, internalizing emotional behaviors, and arithmetic abilities have been identified in GH treated TS girls, compared to non-treated [2]. In our study there were no psychological differences between GH treated and non-treated TS patients, as well as between TS patients receiving and not receiving sex hormone replacement therapy, except better environmental aspect of quality of life in TS patients on sex hormone replacement than those without it. The constellation of neurocognitive and psychosocial deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies, as well as other potential determinants possibly contributing [1]. The main limitation of the study is that numerous variables were examined in a rather small sample size. Besides, there was lack of data regarding somatic health, other medical problems and concomitant medication use for other health problems or diseases because of a poor follow-up of those patients in adulthood. Despite the limitations, our data is important for better understanding of peculiarities of QoL and psychosocial problems associated with Turner syndrome in adult females. In conclusion, after the adjustment for height, weight and body mass index, adult women with TS in Lithuania were found to have impaired cognitive functioning and worse psychological and social aspects of QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women. This data can not be generalized, as it is a representative of adult women with TS in Lithuania, and it could be different if performed in other countries with different culture, religious views, social acceptance and support,
different expectations and possibilities to adapt. These findings reveal the significance of complex inter-relations of psychosocial and biomedical factors in influencing health outcomes. Further studies are needed to increase understanding how inter-relations of psychosocial and biomedical factors determinate well-being of patients with Turner syndrome. Grant support The Research Council of Lithuania, National Research Program of Noncommunicable Diseases financially supported the study (Contract number MIP-048/2015). Acknowledgments The study was financially supported by the Research Council of Lithuania, National Research Program of Noncommunicable Diseases, Contract number: MIP-048/2015. Conflict of interests The authors declare that they have no conflict of interest. References [1] C.H. Gravholt, N.H. Andersen, G.S. Conway, et al., On behalf of the International Turner Syndrome Consensus Group, clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting, Eur. J. Endocrinol. 177 (2017) G1–G70. [2] J. Rovet, Turner syndrome: a review of genetic and hormonal influences on neuropsychological functioning, Child. Neuropsychol. 10 (2004) 262–279. [3] Y.K. van Pareren, H.J. Duivenvoorden, F. Slijper, H.M. Koot, S.L. Drop, S.M. de Muinck Keizer-Schrama, Psychosocial functioning after discontinuation of longterm growth hormone treatment in girls with Turner syndrome, Horm. Res. 63 (2005) 238–244. [4] C. Cullen, D.-A. Ertl, K. Schubert, L. Bartha-Doering, G. Haeusler, Care of girls and women with Turner syndrome: beyond growth and hormones, Endocrine Connect. 6 (2017) (R39-R51.E). [5] E.M. Bannink, H. Raat, P.G. Mulder, S.M. de Muinick Keizer-Schrama, Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome, J. Pediatr. 148 (2006) 95–101. [6] J.C. Carel, C. Elie, E. Ecosse, et al., Self-esteem and social adjustment in young women with Turner syndrome – influence of pubertal management and sexuality: population-based cohort study, J. Clin. Endocrinol. Metab. 91 (2006) 2972–2979. [7] L. Lašaitė, D. Lašienė, L. Lašas, Cognition, emotions and quality of life in Lithuanian girls with Turner syndrome after growth hormone therapy discontinuation, J. Pediatr. Endocrinol. Metab. 23 (2010) 443–450. [8] E.E. Naess, D. Bahr, C.H. Gravholt, Health status in women with Turner syndrome: a questionnaire study on health status, education, work participation and aspects of sexual functioning, Clin. Endocrinol. 72 (2010) 678–684. [9] R.L. Roelofts, E. Wingbermuhle, K. Freriks, C.M. Verhaak, R.P.C. Kessels, J.I.M. Egger, Alexitymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes, Am. J. Med. Genet. A 167 (2015) 768–776. [10] G. Cardoso, R. Daly, N.A. Haq, et al., Current and lifetime psychiatric illness in women with Turner syndrome, Gynecol. Endocrinol. 19 (2004) 313–319. [11] D. Hong, J.S. Kent, S. Kesler, Cognitive profile of Turner syndrome, Dev. Disabil. Res. Rev. 15 (2009) 270–278. [12] A.I. Quintero, E.A. Beaton, D.J. Harvey, J.L. Ross, T.J. Simon, Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes, J. Neurodevel. Dis. 6 (2014) 5–6. [13] K. Lawrence, R. Campbell, J. Swettenham, et al., Interpreting gaze in Turner syndrome: impaired sensitivity to intention and emotion, but preservation of social cueing, Neuropsychol. 41 (2003) 894–905. [14] F. Mazzola, A. Seigal, A. MacAskill, B. Corden, K. Lawrence, D.H. Skuse, Eye tracking and fear recognition deficits in Turner syndrome, Soc. Neurosci. 1 (2006) 259–269. [15] X. Liu, A. Hildebrandt, G. Recio, W. Sommer, X. Cai, O. Wilhelm, Individual differences in the speed of facial emotion recognition show little specificity but are strongly related with general mental speed: psychometric, neural and genetic evidence, Front. Behav. Neurosci. 11 (2017) 149. [16] J. Ross, D. Roeltgen, A. Zinn, Cognition and the sex chromosomes: studies in Turner syndrome, Horm. Res. 65 (2006) 47–56. [17] World Health Organization, United Nations Population Fund, UNICEF, The Reproductive Health of Adolescents: A Strategy for Action: A Joint WHO/UNFPA/ UNICEF Statement, World Health Organization, Geneva, 1989, pp. 1–18. [18] WHO, Physical Status: The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee, World Health Organization, Geneva, 1995, pp. 1–36
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Emotional state, cognitive functioning and quality of life of adult women with Turner syndrome in Lithuania
T
Lašaitė L.a, , Krikščiūnienė R.b, Žilaitienė B.a, Verkauskienė R.a ⁎
a b
Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania Lithuanian University of Health Sciences, Kaunas, Lithuania
ARTICLE INFO
ABSTRACT
Keywords: Turner syndrome Adult patients Emotional state Cognitive functioning Quality of life
Aim: The aim was to analyze emotional state, cognitive functioning and quality of life (QoL) of adult women with Turner syndrome (TS) in Lithuania. Patients and methods: Of all invited adult TS patients from Lithuanian TS database (n = 150), 68 (age 18–60, average 30.2 ± 9.0 years) agreed and were recruited for the study, as well as 68 age-matched healthy control women. Emotional state was evaluated by Profile of Mood States (POMS) questionnaire, cognitive functioning by Trail Making Test and Digit Span Test (DST) of Wechsler Adult Intelligence Scale, and QoL by WHO Brief Quality of Life Questionnaire (WHO QoL). Results: Patients with TS were of a significantly shorter stature (p < .001) than age-matched control women and than the 3rd percentile of the National Standards of Lithuania. After the adjustment for height, weight and body mass index (BMI), no significant differences in emotional state were detected, though without the adjustment, depression-dejection (p = .004) score was significantly higher in TS women than in age-matched controls. Significantly worse cognitive functioning (attention capacity, visual scanning abilities, executive function and psychomotor speed, p < .001), as well as worse psychological (p = .002) and social (p = .006) aspects of QoL were found after the adjustment for height, weight and BMI in adult women with TS than in age-matched controls. Conclusion: In conclusion, after the adjustment for height, weight and BMI, adult women with Turner syndrome in Lithuania have impaired cognitive functioning and worse psychological and social aspects of QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women.
1. Introduction Turner syndrome (TS) is a rare (affecting 25–50 per 100,000 females) genetic disorder that arises from a partial or complete loss of X chromosome material [1]. It is associated with a number of characteristic physical features (such as short stature, gonadal dysgenesis, lack of pubertal maturation, infertility, kidney and cardiac anomalies and others), as well as a particular social and behavioral features, a particular neurocognitive profile, deficits of memory, attention, social cognition and emotional recognitions [1,2]. In case of TS, it is common practice to treat short stature with growth hormone (GH) preparations and to induce puberty with estrogens at an age as close to normal puberty as possible in case TS girls do not go through spontaneous puberty [1]. But results of some studies show that even after reaching a height within the normal range and puberty induction at a pubertal age, some women with TS still
⁎
experience psychosocial problems and lower QoL [3]. Many factors can affect their emotional state, cognitive functioning and QoL, such as increased marginalization by peers or self-marginalization, low selfesteem due to short stature or bullying, and other factors that might vary in different cultures. Usually adult women with TS not only experience a decreased health status, but also manifold psychosocial difficulties [4]. Some studies found normal QoL in young adult women with TS who reached normal height after GH therapy and had age-appropriate pubertal development [5]. On a large cohort study of women with TS treated by GH during childhood, Carel et al. [6] showed that their selfesteem and social adjustment were impacted by the comorbidities (such as hearing loss and heart diseases). In our previous study with a very small sample size, we found patients with TS in their adolescence and emerging adulthood after GH therapy discontinuation to have altered emotional state, impaired cognitive functioning and lower QoL than
Corresponding author. E-mail addresses: [email protected], [email protected] (L. Lašaitė).
https://doi.org/10.1016/j.ghir.2019.03.001 Received 31 August 2018; Received in revised form 22 February 2019; Accepted 17 March 2019 Available online 18 March 2019 1096-6374/ © 2019 Elsevier Ltd. All rights reserved.
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their healthy peers [7]. In older adult TS women no impairments in QoL were detected, except in the subscales of physical functioning, general health and social isolation [8]. Patients with TS usually show higher levels of alexitymia, more shyness, social anxiety, and lower self-esteem than those without TS. Also they score lower in tests on self-perception and attitude towards their body than normally developing girls, even after they achieve a height in the lower normal range with GH therapy [3,9]. Depression is rather prevalent psychiatric diagnosis in TS adults [10]. This psychological profile leads to a weaker social relationships and lower QoL [1,10]. Although their intelligence quotient (IQ) and verbal abilities are usually normal, some women with TS show impaired visual-spatial and spatial-numerical processing or disabilities affecting recognition or executive functions [11]. Deficits in executive functioning may include problems in switching attention between tasks, planning, inhibiting innapropriate responses and working memory (the transient holding, processing and manipulation of information) [11,12]. Reduced processing speed is also a frequent finding [12]. As a consequence of that, in addition to health-related problems, social interaction of TS women may be affected by difficulties in interpreting non-verbal communication, recognizing facial expression of certain emotions [13,14]. Human facial expressions are important social signals and provide a large variety of socially relevant information. So, face perception and emotion decoding are abilities of great importance in everyday life [15]. Impairments in social skills and affective discrimination characterize a substantial proportion of TS females, who possess limited numbers of friends and who experience social isolation as well as poor self-concept [16]. The aim of medical care and therapy should focus not only on the patient‘s physical health, but also on his psychosocial state and QoL. Data on different psychological aspects in patients with TS is still rather controversial. The aim of the study was to analyze emotional state, cognitive functioning and QoL in adult women with Turner syndrome in Lithuania.
A total of 68 age-matched healthy women were recruited for the control group of the study. They were randomly selected from those who arrived to the out-patient department and were found to have normal thyroid function and no other endocrine dysfunctions. Besides, no one of them had neither comorbid psychiatric disorders (such as major depressive disorder, dementia or anxiety disorder), nor any organic cerebral disorder, nor any chronic uncontroled/ untreated somatic disease at the period of the beginning of the study.
2. Subjects and methods
The Profile of Mood States (POMS) questionnaire was used for evaluation of emotional state of the participants [21]. It is a self-reported psychological measurement of immediate mood states. The POMS is a 65-item mood adjective checklist in which, using a five-point Likert-type scale, each adjective is scored from 0 (absent) to 4 (very much) based on how well each item describes the respondent's mood during the certain time frame (during the past week, including today). Following standard scoring methods, six mood scales are derived: tension-anxiety, depression-dejection, anger-hostility, vigour-activity, fatigue-inertia and confusion-bewilderment. A higher score denotes a higher level of certain emotion. Cognitive functions were assessed by Trail Making Test [22] and Digit Span Test (DST) of Wechsler Adult Intelligence Scale [23]. The Trail Making Test is a timed test in which the subject connects an altering sequence of numbers (Trail Making A) or numbers and letters (Trail Making B) in ascending order. The score on the Trail Making A test, which is based on time required to complete the sequence, is a measure of attention and visual scanning abilities, and Trail Making B is a test of executive function and psychomotor speed. A higher score denotes worse cognitive functioning. The Digit Span Test is a test in which the subject repeats sequences of numbers in a given order. The score of the test is a number or repeated number sequences in forward order and backward order. The test shows attention capacity and psychomotor speed. A higher score denotes better cognitive functioning. Generic WHO Brief Quality of Life Questionnaire (WHO QoL) questionnaire [24] was used for the QoL assessment. It consists of 26 questions and measures four subscales of quality of life: physical, psychological, social and environmental. A higher score represents better QoL.
2.2. Objective data The study was approved by Kaunas Regional Ethics Committee of Biomedical Research (No BE-2-32, 2014-06-03). All procedures were carried out with the adequate understanding and written consent of the subjects. The investigation was carried out in accordance with the Declaration of Helsinki. Anthropometrical measurements were made according to WHO guidelines [18]. Body mass index (BMI) was calculated as weight (kg)/ height (meters) squared [19]. Height and weight were compared to the National Standards of Lithuania [20]. Morning fasting vein blood samples of TS patients and of control women were taken. Serum was separated and stored at −20 °C until analyzed. Concentrations of insulin like growth factor −1 (IGF-1) (Biosource, Belgium), testosterone (Biosource, Belgium), thyroid stimulating hormone (TSH) (Immunotech, Czech Republic), free thyroxin (FT4) (Immunotech, Czech Republic) were measured by radioimmune assay. Luteinising hormone (LH) (Biosource, Belgium), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) (Immunotech, Czech Republic), estradiol (E2) (Immunotech, Czech Republic), dehidroepitestosterone - sulfate (DHEAS) (Immunotech, Czech Republic) were measured by immunoradiometric assay. 2.3. Psychological assessment
2.1. Subjects According to a Joint WHO/UNICEF Statement, the adult person is older than 18 years old [17]. Patients from the TS database of Lithuania who were older than 18 years at the time of the beginning of the study were invited to participate in the study. Of all invited 150 adult TS patients, 72 (48%) agreed to participate. Because of the previously diagnosed mental retardation, four women could not be recruited for the study. Other 78 (52%) invited TS patients did not respond (one of the possible explanations could be the high level of emigration from Lithuania). Patients with TS who did not respond were not researched, so it is not possible to know are there any differences in physical health, psychological state and QoL of the responders and non-responders. A total of 68 women diagnosed with genetically confirmed TS (66.2% 45, X0, and 33.8% non-45,X0, including mosaicism and izochromosome) were recruited for the study. Of all 68 TS women, 53 (77.9%) underwent GH therapy before (at least 6 months prior to the begining of the study). Their GH therapy lasted for at least one year until discontinuation after fusion of epiphyseal growth plates. The median duration of GH treatment was 3 years (25th – 75th percentile 1–6 years, average 3.26 years). Other 15 (22.1%) TS women did not recieve GH therapy because of the delayed diagnosing or sufficient adult height (n = 2, mean adult height 168 ± 0.8 cm). Also 34 (50.0%) of the researched patients were on natural estrogens, 18 (26.5%) were using oral combined contraceptive pills, and 16 (23.5%) were not receiving any sex hormone replacment therapy at the enrollement into the study. If required, all patients were on a stable and adequate adrenal and/or thyroid replacement. 38
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the mentioned significance disappeared after the adjustment for height, weight and BMI. So, no significant differences in emotional state were detected after the adjustment for height, weight and BMI. Both tests of cognitive functioning showed worse attention capacity, visual scanning abilities, executive function and psychomotor speed in patients with TS than in age-matched controls. The significance remained the same after the adjustment for height, weight and BMI (Table 3). Comparing QoL between women with TS and age-matched control women (Table 3), significant differences were detected in all subscales except environmental. Evaluations of physical, psychological and social subscales were significantly lower (meaning worse QoL) in adult women with TS than in control women. After the adjustment for height, weight and BMI, significance disappeared in physical scale. So, after the adjustment for height, weight and BMI, scores of psychological and social subscales were significantly lower (meaning worse QoL) in adult women with TS than in age-matched control women (Table 3). The group of the researched adult TS patients who were receiving sex hormone replacement therapy (n = 52), differed only in the environmental aspect of QoL (median 15.5 vs. 14.5, p = .020), but not in emotional state, cognitive functioning, other aspects of QoL (physical, psychological, social) from the TS patients who were not receiving any sex hormone replacement (n = 16). The group of the adult TS patients who did not undergo GH therapy before the beginning of the study (n = 15), were not significantly different in terms of emotional state, cognitive functioning, QoL from the TS patients who underwent GH therapy (n = 53). However, the stature of patients who recieved GH therapy was significantly higher when compared to untreated (median 152 cm vs. 148 cm, p = .016). No significant differences in terms of emotional state, cognitive functioning, QoL were found between the group of TS patients with 45, X0 (n = 45) and with non-45, X0 (n = 23) karyotypes. Significant correlations in adult women with TS were found between hormone concentrations and psychological state data (Table 4). FT4 concentration correlated negatively with emotional state (tensionanxiety, depression-dejection, fatigue-inertia, confusion-bewilderment), and positively with physical aspect of QoL. TSH concentration correlated positively with fatigue-inertia, and negatively with psychological aspect of QoL. Testosterone concentration correlated with psychological aspect of QoL, and negatively with cognitive functioning (attention capacity, visual scanning abilities, executive function and psychomotor speed). IGF − 1 concentration correlated positively with fatigue-inertia. DHEAS concentration correlated with cognitive functioning (attention capacity, visual scanning abilities). LH concentration correlated with cognitive functioning (attention capacity).
Table 1 The main anthropometric characteristics of adult women with Turner syndrome and age-matched control women. Categories
TS patients (n = 68), median (25th – 75th percentile)
Controls (n = 68), median (25th – 75th percentile)
p
Age, years, Height, cm, Weight, kg, Body mass index, kg/m2
29.0 (23.0–36.0) 151.7 (148.0–156.0) 56.0 (50.0–63.1) 23.9 (21.9–27.1)
29.0 (23.0–37.0) 168.0 (163.7–171.7) 61.0 (53.7–66.8) 21.8 (19.4–24.0)
0.807 < 0.001 0.023 < 0.001
2.4. Statistical analysis Analysis was performed using SPSS 23.0 software. The values are given as median and 25th–75th percentile. As the analyzed values were non-normally distributed, the differences between the means in groups were calculated using Mann-Whitney test as well as χ2 test. Adjustment for height, weight and BMI was performed by the Univariate Analysis of General Linear Model. Associations between somatic, hormonal and psychological data were determined using Spearman correlation coefficient. The limit of significance was defined as a two-sided p-value lower than 0.05. 3. Results Results of the main anthropometric characteristics of the study subjects with TS and age-matched controls are presented in Table 1, and their social characteristics in Table 2. Regarding the social state, less women with TS had university education, less were employed and more unemployed than the age-matched control women. Less women with TS were married or cohabiting and less of them had children (their own or adopted) than the control women. Patients with TS were of a significantly shorter stature than the control women (Table 1). The median height of TS patients was lower than the 3rd percentile of the National Standards of Lithuania (156.0 cm). The median height of age-matched control women was between the 50th and 75th percentile (163.0–171.0 cm) of the National Standards of Lithuania [20]. Weight of patients with TS was significantly lower and BMI was significantly higher than of the control women (Table 1). The median weight of adult women with TS was higher than the 10th percentile (51.0 kg) of the National Standards of Lithuania. The median weight of age-matched control women was slightly higher than the 50th percentile (60.0 kg) of the National Standards of Lithuania [20]. Regarding the emotional state (Table 3), depression-dejection was significantly higher in TS women than in control women, but no significant differences were found in tension-anxiety, anger-hostility, vigour-activity, fatigue-inertia and confusion-bewilderment. However,
4. Discussion The results of our study after the adjustment for height, weight and BMI revealed that adult women with TS in Lithuania have impaired cognitive functioning and worse psychological and social aspects of
Table 2 The main social characteristics of adult women with Turner syndrome and age-matched control women. Categories Education, n (%) Employment, n (%) Matrital status, n (%) Children, n (%)
Lower than university University Employed Studying Unemployed Single Married or cohabiting Divorced or separated or widowed Birth Adoption No children
TS patients (n = 68)
Controls (n = 68)
p
44 (64.7) 24 (35.3) 39 (57.3) 14 (20.6) 15 (22.1) 39 (57.3) 25 (36.8) 4 (5.9) 3 (4.4) 1 (1.5) 64 (94.1)
23 (33.8) 45 (66.2) 48 (70.5) 17 (25.0) 3 (4.5) 13 (19.2) 50 (73.5) 5 (7.3) 33 (48.4) 0 35 (51.6)
< 0.001 (χ2 = 21.5)
39
0.005 (χ2 = 10.7) < 0.001 (χ2 = 16.2) < 0.001 (χ2 = 32.2)
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Table 3 Emotional state, cognitive functioning and quality of life in adult women with Turner syndrome, compared to age-matched control women. Categories
TS patients (n = 68), median (25–75 percentile)
Controls (n = 68), median (25–75 percentile)
P value
P value (adjusted for height, weight and BMI)
POMS, tension-anxiety⁎ POMS, depression-dejection⁎ POMS, anger-hostility⁎ POMS, vigour-activity⁎ POMS, fatigue-inertia⁎ POMS, confusion-bewilderment⁎ Trail Making A test ⁎⁎ Trail Making B test ⁎⁎ DDS forwards ⁎⁎* DDS backwards ⁎⁎* WHO QoL, physical ⁎⁎** WHO QoL, psychological ⁎⁎⁎* WHO QoL, social relations ⁎⁎⁎* WHO QoL, environmental ⁎⁎⁎⁎
4.5 (2.0–8.7) 6.5 (3.0–11.0) 6.5 (4.0–9.0) 17.0 (15.0–19.0) 5.0 (3.0–8.0) 2.0 (−0.7–4.0) 37.0 (31.0–54.2) 85.5 (67.7–101.7) 5.5 (4.0–7.0) 4.0 (4.0–5.0) 16.0 (14.8–16.6) 14.7 (13.5–15.3) 14.7 (13.3–16.0) 16.0 (15.0–16.5)
3.0 (1.0–7.0) 3.0 (2.0–7.7) 7.0 (4.0–9.7) 18.0 (16.0–21.0) 6.5 (4.0–9.7) 1.5 (−1.0–3.0) 26.0 (21.0–30.0) 53.0 (43.0–63.0) 7.0 (6.0–9.0) 7.0 (5.0–8.0) 16.6 (15.4–17.1) 15.3 (14.2–16.0) 16.0 (14.7–16.0) 16.0 (15.0–16.5)
0.232 0.004 0.339 0.084 0.118 0.337 < 0.001 < 0.001 < 0.001 < 0.001 0.014 0.001 < 0.001 0.957
0.248 0.141 0.675 0.145 0.516 0.245 < 0.001 < 0.001 < 0.001 < 0.001 0.077 0.002 0.006 0.449
A higher score denotes a higher level of certain emotion. A higher score denotes worse cognitive functioning. ⁎⁎⁎ A higher score denotes better cognitive functioning. ⁎⁎⁎⁎ A higher score denotes better quality of life. ⁎
⁎⁎
aspects of QoL, but not physical were worse in TS women compared to age-matched control women after the adjustment for height, weight and BMI (though if not adjusted, physical aspect of QoL was worse as well). Sutton et al. [27] suggested that short stature affects almost all TS women, either because they endured teasing over the years or were discouraged or frustrated by their dependence on other people to performe different tasks. TS patients show deficits in their emotional well-being as well as in their social functioning. Studies on the incidence of anxiety or depression in women with TS show conflicting data, possibly due to selection bias, disparate outcome measures and small sample sizes [28,29]. In general, women with TS experience lower self-concept compared to women without TS [28,30]. In our study we were not able to detect differences in emotional state between TS women and age-matched controls after the adjustment for height, weight and BMI, though without the adjustment depresion-dejection score was higher in TS women. Data is contradictory on QoL associations with vocational training and employment in TS women. Less employment or employment below the women's vocational training lead to lower overall life satisfaction correlated to professional life than in control women [31]. In contrast, some studies have reported educational achievements and job levels in women with TS equal [6] or even above that of the average female population [32]. In our study 22.1% of adult TS women reported to be unemployed, while in Lithuanian adult population unemployment level is 7.3% and in Lithuanian female population 5.7% [33]. Social functioning may also be hindered by specific cognitive profile in TS women with marked deficits in various visual-spatial and visualmotor skills, arithmetic abilities, executive functions and some language aspects, while other intellectual capacities are usualy preserved in TS [2,16,34]. Studies on psychomotor function suggest both general and specific motor impairments in TS, including dificulties in visualmotor coordination, learning and fine motor function [35]. In our study we found adult women with TS performing significantly worse in such aspects of cognitive functioning as attention, visual scaning abilities, executive function and psychomotor speed compared to age-matched control women. Several functional magnetic resonance imaging studies showed that TS women fail to incorporate frontal, executive functions related brain regions during performing visual tasks. Working memory difficulties in TS are related to differences in functional connectivity between parietal and frontal regions [36,37]. Neuroimaging studies in TS revealed abnormalities in several brain areas, known to be involved in emotional processing as well [38,39]. Lepage et al. [40] found that socio-emotional functioning in TS patients
Table 4 Significant correlations between hormone concentrations and psychological data in adult women with Turner syndrome. Significant correlations between POMS, fatigue-inertia POMS, fatigue-inertia WHO QoL psychological POMS, tension-anxiety POMS, depression-dejection POMS, fatigue-inertia POMS, confusion-bewilderment WHO QoL physical Trail Making A DDS forwards Trail Making A Trail Making B WHO QoL psychological
IGF - 1 concentration TSH concentration TSH concentration FT4 concentration FT4 concentration FT4 concentration FT4 concentration FT4 concentration DHEAS concentration LH concentration Testosterone concentration Testosterone concentration Testosterone concentration
r
p
0.298 0.263 - 0.280 - 0.293 - 0.303 - 0.390 - 0.288 0.257 −0.442 −0.327 −0.465 −0.426 0.260
0.032 0.039 0.026 0.020 0.016 0.002 0.022 0.042 0.006 0.009 0.003 0.006 0.045
QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women. The data presented are representative of adult women with TS in Lithuania, and it could be different if performed in other countries with different culture, religious views, social acceptance and support, different expectations and possibilities to adapt. We also found young adult women with TS to have lower height and weight and higher BMI than age-matched controls as well as the standard height and weight of the National Standards of Lithuania [20]. Usually untreated women with TS are approximately 20–21 cm shorter than healthy women within the respective population. Use of GH in usual doses increases growth in TS girls by approximately 3 cm in the first year of treatment and by approximately 2 cm per year after 2 years of treatment. Despite this increase, the final height of GH treated TS women usually is still outside the normal range [25]. In our study Lithuanian adult TS women had median height 151.7 cm, being approximately 11–12 cm less than 50th percentile (163.0 cm) of the National Standards of Lithuania [20]. Height gain from GH treatment in TS patients was found not to be associated with QoL scores, however, low QoL being related to the degree of short stature, although this can vary considerably and is dependent on the individual attitudes of patients [5]. Health-related QoL was shown to be worse in adult TS women than in general population and in age-matched control women in physical functioning domains, but not in psychological [26]. We did not find relation of height to any domain of QoL or emotional state. In our study psychological and social 40
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is related to their aberrant brain morphological structures. However, it is hard to determine whether the brain‘s unique morphological and activation patterns, observed in TS, are the cause of their social difficulties or the consequence of it. The brain serves as an endophenotype that bridges the gap between molecular genetics and complex behavior [41]. As demonstrated by genomic data, many X-linked genes are involved in postsynaptic protein coding, which is essential for neuronal plasticity and cognitive processes [42]. The X-linked genes have increased expression level in brain tissues, which supports an essential role of the X chromosome in brain development and mental functioning [43]. Relationships between specific brain phenotypes and behavioral-cognitive abilities may be altered in TS patients, and X chromosome loss may moderate brain relationships to behavior and cognition [39]. Approximately half of TS individuals exibit a complete loss of one X chromosome, termed X-monosomy (45, X0 karyotype), whereas approximately 10% of TS individuals exibit structural abnormalities in one of the two X chromosomes or more complex X chromosome abnormalities [44]. Physical and psychological features highly vary across women with TS as a result of the varied structural defects of the X chromosome or mosaicism [45]. In general, small deletions on the X chromosome or mosaicism likely manifest fewer and subtler TS features, whereas large deletions, or non-mosaicism karyotypes may result in the full spectrum of TS features. Most typical TS phenotypes are expected to occur in women who express a 45, X0 karyotype [45]. In our study we failed to detect psychological differences between TS patients with 45, X0 karyotype and with non-45, X0 karyotype, possibly because of a small sample size. Hormone deficiency might also impact brain regions involved in affect regulation and behavior [46]. Several studies have demonstrated significantly better visual-perceptual and visual-spatial abilities, motor planning skills in estrogen treated TS patients than in non-treated [2,47]. Ross et al. [48] suggested that these results reflect a specific influence of estrogen on brain maturation during puberty. More recent studies have demonstrated that brain morphometric changes during puberty are at least, in part, driven by estrogen [49,50]. But by adulthood, endogenous or exogenous estrogen has limited impact on modifying cognitive differences that likely arise much earlier in development [51]. Slightly better performance in psychological functioning, internalizing emotional behaviors, and arithmetic abilities have been identified in GH treated TS girls, compared to non-treated [2]. In our study there were no psychological differences between GH treated and non-treated TS patients, as well as between TS patients receiving and not receiving sex hormone replacement therapy, except better environmental aspect of quality of life in TS patients on sex hormone replacement than those without it. The constellation of neurocognitive and psychosocial deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies, as well as other potential determinants possibly contributing [1]. The main limitation of the study is that numerous variables were examined in a rather small sample size. Besides, there was lack of data regarding somatic health, other medical problems and concomitant medication use for other health problems or diseases because of a poor follow-up of those patients in adulthood. Despite the limitations, our data is important for better understanding of peculiarities of QoL and psychosocial problems associated with Turner syndrome in adult females. In conclusion, after the adjustment for height, weight and body mass index, adult women with TS in Lithuania were found to have impaired cognitive functioning and worse psychological and social aspects of QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women. This data can not be generalized, as it is a representative of adult women with TS in Lithuania, and it could be different if performed in other countries with different culture, religious views, social acceptance and support,
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