Sex Hormone Levels and Cognitive Verbal Performance in Patients with a
Schizophrenia Spectrum Disorder
Womei Lekranty Universiteit van Amsterdam
Sex Hormone Levels and Cognitive Verbal Performance in Patients with a Schizophrenia Spectrum
Disorder
Abstract
Schizophrenia spectrum disorder (SSD) affects ~1% of all people worldwide and reduces the quality of life measured in lost healthy years more than any other disorder. Language and cognitive impairments are widely observed in SSD patients and can result in reduced social and economic functioning. Evidence suggests that sex hormones, estrogen and testosterone, can be used to explain sex differences in the severity and course of SSDs. In this study, we aimed to evaluate the relationship between serum sex hormone levels and cognitive and verbal performance in SSD patients. 110 patients (77.7% male) with chronic SSD participated in the study. We evaluated the
correlation of serum estrogen and testosterone levels with cognitive and verbal performance in males and females, additionally adjusting for years of education. For this, we used verbal memory and verbal fluency scores of the Brief Assessment of Cognition in Schizophrenia (BACS) and used computational algorithms to collect syntactic complexity and speech rate scores from patients. No significant
correlations were found between estrogen or testosterone and verbal/ cognitive performance in males. Significant effect of testosterone adjusted for years of education was found on verbal memory performance. In females, we observed a significant inversed correlation between estrogen and speech rate. These results suggest that further research on this subject needs to be done to elucidate relationships between serum sex hormone levels and cognitive, verbal performance in SSD patients. Moreover, in future research on the relationship between verbal memory and testosterone levels in SSD males, years of education could be taken into account for more significant outcomes.
Keywords: Schizophrenia Spectrum Disorder (SSD), sex hormones, estrogen, testosterone, cognition, language impairment, verbal memory,
verbal fluency, syntactic complexity, speech rate.
1. Introduction
Schizophrenia spectrum disorder (SSD) is a severe psychiatric disorder, affecting ~1% of the global population (Kuperberg, 2010). The disorder is characterized by a great variety of symptoms that have a serious impact on many aspects of patients’ everyday life. For example, this impact is reflected in the high unemployment rates (70-92%) that are observed in SSD patients, and the often-seen inability to complete higher education within this patient group (Ritsner, 2011; Hakulinen et al., 2019). Also, it appears that SSD patients report a low quality of life (QOL) on physical, psychological, environmental, and especially on social domains (Solanki et al, 2008). The lowest scores were found related to the social domain, despite treatment with antipsychotics. In comparison to other disorders, SSD is one of the most disabling disorders worldwide when it comes to disability-adjusted years of life (DALY’s), or, the lost years of “healthy” life, measured in number of years lost due to
disability of the disease and years lost due to premature death(Salomon et al., 2012). It is expected that 4.9 percent of all schizophrenic patients will commit suicide (Bushe et al., 2010; A Palmer et al., 2012).
The severity of schizophrenia can be associated with the great variety of symptoms of the disease. Symptoms of schizophrenia are commonly classified into three categories: positive symptoms, negative symptoms and cognitive deficits. Positive symptoms are additions to- or
distortions of normal functioning and include hallucinations, delusions and disorganized speech or formal thought disorder (FTD). Negative symptoms, however, describe the reduction of normal functioning, such as lack of motivation, apathy and speech and language deficiencies. Cognitive deficits, such as impairments in verbal memory, attention, and processing speed, are also often observed in schizophrenia patients. (American Psychiatric Association, 2013). While treatment with antipsychotics reduces positive symptoms, negative and cognitive symptoms often persist in many cases (Tandon, Nasrallah, Keshavan, 2009; Miyamoto, Miyake, Jarskog, Fleischhacker, Lieberman, 2012).These cognitive impairments have been found to be closely related to and even potentially cause many of the social and economic problems that schizophrenics face (Keefe & Harvey, 2012).
This last category of symptoms, cognitive impairment, is a core characterization of SSD. Verbal memory and verbal fluency both are strong predictors of the severity of cognitive disability in SSD patients (Ojeda, Pena, Sánchez, Elizagárate, & Ezcurra, 2008; Hofer et al., 2005). Moreover, deficits in these domains are among the most prevalent cognitive impairment in SSD patients (Heinrichs, & Zakzanis, 1998; Wilk et al., 2005). Also, verbal fluency performance is significantly impaired in both SSD patients and in ultra-high risk (UHR) patients and may therefore predict psychosis in these UHR patients (Beckeret al., 2010). These cognitive impairments, that both rely on verbal skills, are closely related to language deficits, which are also widely observed in SSD patients (Kuperberg, 2010).
Language deficits in schizophrenia can also be observed more directly through speech impairment and are key symptoms observed in patients with SSD, which have a major impact on social functioning (de Boer, Brederoo, Voppel, & Sommer, 2020; Oliveira, Esteves, & Carvalho, 2015). More specifically, it is found that patients with SSD show less complex speech on a syntactic level compared to healthy
subjects, and tend to produce shorter and simpler sentences, possibly due to cognitive impairment (Kuperberg, 2010; Özcan et al., 2016; Kircher, Oh, Brammer, & McGuire, 2005). Research suggests that the absence of neural complex speech patterns in SSD patients, correlates with reduced activation in the right middle temporal cortex and superior frontal cortex. As opposed to SSD patients, in healthy controls these areas are more active and correlate with the production of more complex speech (Kircher et al., 2005). This biological substantiation for impaired complexity of speech in SSD patients, is in line with a study that showed syntactic complexity seems to cosegregate within family members with SSD, in contrast to their healthy family members (DeLisi, 2001). Furthermore, a recent study that compared language in SSD patients with healthy controls found that SSD patients tend to speak less and articulate slower (De Boer et al., 2020). In line with this, schizophrenic speech contains more pauses and hesitations (Cohen, Mitchell, & Elvevag, 2014). This decreased speech rate is often used as an indicator for impaired fluency of speech (Covington et al., 2005; De Jong & Wempe, 2009; Kormos & Denes, 2004). In summary, verbal and cognitive performance in SSD patients are consistently found to be impaired through reduced verbal memory, reduced verbal fluency performance, and reduced syntactic complexity and rate of speech.
Furthermore, it is known that robust sex differences exist that affect the severity of many aspects of schizophrenia, including symptoms, age of onset, and the course of the disease (Sommer, Tiihonen, van Mourik, Tanskanen, & Taipale, 2020). Men have an overall 50% greater chance to develop schizophrenia (McGrath et al., 2004), and have an earlier age of onset than women with schizophrenia (Seeman, 2020). Women suffer on average less negative symptoms than men (Sommer et al., 2020) and seem to respond better to antipsychotic treatment
(Begemann, Decker, Lunenberg, & Sommer, 2012). Also, it is found that female SSD patients outperform men in several cognitive performance tests, including verbal memory (Ayesa-Arriola et al., 2014).
A very likely explanation for these sex differences is the role of sex hormones, specifically estrogen, on different aspects of SSD (Gogos et al., 2015). Estrogen is thought to play a protective role affecting several key aspects of schizophrenia. Reduced estrogen levels are associated
with increased symptom severity, despite treatment with antipsychotics (Gogos et al., 2015). Studies have shown that male and female SSD patients with lower estrogen levels perform less well on cognitive functioning tests (Ko et al., 2006; Hoff et al., 2001). The positive correlation between estrogen levels and cognitive functioning in women is especially evident in verbal fluency and memory task performance, showing that higher estrogen levels are associated with better verbal fluency and -memory performance (Miller et al., 2002; Halari et al., 2004). Several other studies have shown that augmentation of estrogen levels correlate with better cognitive performance in men (Kulkarni, Gavrilidis, Worsley, Van Rheenen, & Hayes, 2013). Additionally, estrogen receptor expression is decreased in both male and female SSD patients, when compared to healthy controls, which may contribute to an increased risk of SSD (Weickert et al., 2008).
Similarly, other studies show that the male sex hormone, testosterone, is increased in female patients, and decreased in male patients when compared to their healthy counterparts (e.g. Misiak et al., 2018). Also, circulating testosterone levels appear to be lower in schizophrenia patients that show more negative symptoms, and these testosterone levels are inversely correlated with the severity of negative symptoms in male patients (Akhonzadeh et al., 2006; Goyal et al., 2004). Additionally, Moore et al. (2013) found that free testosterone levels and can predict performance on multiple cognitive domains, including verbal memory, in male SSD patients. This research also showed that years of education significantly predicted verbal memory performance in male SSD patients.
In SSD, language and communication are of great importance on social functioning and interaction (Oliveira, Esteves, & Carvalho, 2015). The decreased complexity, rate of speech, and impaired verbal productivity and cognition, as discussed above, can predict social skills, social engagement and the existence of friendships in SSD patients (Bowie & Harvey, 2008; Bowie, 2011). Since language impairments are widely observed in SSD patients (Kuperberg, 2010), it is important to investigate these impairments to improve (early) diagnosis of SSD and improve quality of life in this patient group. SSDs are commonly diagnosed clinically, leaving room for subjective interpretation of the
diagnosis, while more objective quantitative biomarkers, such as hormonal biomarkers, may result in more sufficient anamnestic information. As discussed above, previous research shows that serum estrogen and testosterone levels are related to verbal fluency and verbal memory. Similar to the diagnosis of SSD, the diagnosis of cognitive defects of SSD patients takes significant time and may be influenced by a clinician’s bias. Here we research the relationship between cognitive, speech, and verbal impairment and sex hormone levels in SSD patients, using a computer-based approach that uses spontaneous speech production and automatically calculates speech rate and syntactic complexity of speech. Our hypothesis is that higher estrogen levels will correlate with better cognitive performance and increased syntactic complexity in both female and male SSD patients, and that increased testosterone levels in males will be associated with better cognitive verbal performance.
Most research on the relationship between estrogen and verbal cognitive performance in SSD patients has been done in female patients, whereas the relationship between testosterone and verbal cognitive performance has been researched mainly in male SSD patients. In the current study, the effects of both estrogen and testosterone levels on verbal memory and – fluency, and syntactic complexity and speech rate in male SSD patients were investigated. Also, the effects of estrogen on verbal memory and – fluency, and syntactic complexity and speech rate was investigated in female patients. Lower estrogen levels in SSD patients are expected to correlate with lower scores on the beforementioned cognitive areas. Measurement of syntactic complexity often relies on subjective rating scales for symptoms, often taking significant amounts of time. In this study we have used a machine learning algorithm to measure syntactic complexity without the presence and bias of a clinician (De Boer et al., 2020). Using this computerized language analysis, and hormonal biomarkers, we aim to elucidate the relationship between sex hormones and verbal cognitive performance.
2. Methods
For the current study, baseline data was derived from a study population participating in an ongoing randomized placebo-controlled double-blind trial “Raloxifene Augmentation in Patients with a Schizophrenia spectrum Disorder (RAPSODI)” (Brand et al., 2020). In this medication study, participants were administered 120 mg/day raloxifene for twelve weeks. The Rapsodi study is carried out in accordance with the ethical
standards of the Declaration of Helsinki and International Conference on Harmonization.
2.1 Participants
Approximately 110 participants, aged over 18 years, were recruited from the in- and outpatient clinics throughout the Netherlands between November 2016 and September 2020. Primarily, all participants were capable of understanding the purpose and details of the study in order to provide written informed consent. All participants were clinically diagnosed on basis of the DSM-IV-R (SCID) with a schizophrenia spectrum disorder: DSM IV diagnosis of 295.x: schizophrenia, schizophreniform disorder, schizoaffective disorder or 298.8; a not otherwise specified psychosis-related disorder (psychotic disorder NOS). To confirm the diagnosis of the participants, the Mini International
Neuropsychiatric Interview 5.0.0. (M.I.N.I. Plus; Sheehan et al. 1998) was administered. In all participants, antipsychotic medication usage and dose was stable for two weeks prior to the study. Female participants that were of childbearing potential were excluded from participation or were to use a non-estrogenic contraceptive. Female participants that were pregnant or breastfeeding were excluded. Participants who used estrogen or androgen hormonal medication within three months prior to the study were also excluded from participating. Participants of which speech production was assessed additionally, were only allowed to participate if their mother tongue was Dutch. Participants with an uncorrected hearing impairment or a speech impediment, like stuttering, were not allowed to participate. Participants were also excluded if they had missing verbal memory or verbal fluency scores and did not finish the speech interview, or if they had missing or outlying estradiol and testosterone levels.
2.2 Measurements
2.2.1 Verbal Performance – cognition
For the present investigation, verbal memory and verbal fluency were scored from each participant by using the Brief Assessment of Cognition in Schizophrenia (BACS; Keefe et al. 2004).
Verbal Memory
Verbal memory was assessed by list learning: the participants were verbally presented 15 words, after which they had to verbally recall as many as possible. This was repeated five times with the same words. The total score of verbal memory was measured as the sum of correctly recalled words per trial, in any order.
Verbal Fluency
Verbal fluency was assessed by asking the participants to generate as many words as possible in a certain category under 60 seconds. In the first trial participants were asked to name as many animals as possible. In the subsequent two trials, the participants were asked to generate as
many words as possible that begin with a certain letter, also under 60 seconds. In the first trial, the letter ‘V’ was given, in the second trial the letter ‘S’ was given. The total score of verbal fluency was equal to the sum of unique answers in all three trials.
2.2.2 Verbal Performance – speech production
Syntactic complexity: D-level
To measure syntactic complexity of speech in participants, the recordings of the participants speech were transcribed manually using Wreally (https://transcribe.wreally.com). The transcriptions were analyzed by T-Scan (Pander Maat et al., 2014): a software tool for the analysis of Dutch texts. For this analysis, all transcriptions were adjusted to fit the right requirements for the T-Scan run as described in the manual “Handleiding T-Scan” (Pander Maat, Kraf & Dekker, 2017, p. 6). Subsequently, T-Scan scored Development Levels (D-levels); a measure for syntactic complexity designed by Rosenberg & Abbeduto (1987). The D-level scale, consisting of eight levels (level 0 to 7), classifies and ranks sentences based on their complexity. The sentence constructs’ complexity is ranked based on the chronological order in which children learn how to use these constructs. Level 0 being the least complex construct form, and level 7 being the most complex construct form. T-Scan scored D-level per sentence and subsequently average D-level at text level.
Speech rate
To assess speech rate in participants, the recordings were analyzed with Praat software (Boersma & Weenink, 2018); a computer program that analyses spontaneous Dutch speech, without the need for transcriptions, using a script written by De Jong & Wempe (2009) that automatically measures speech rate expressed as produced number of syllables per speech time in seconds. Speech rate is defined as the rate of speaking, which also includes hesitations and pauses, and laughing, during which syllables can still be detected.
2.3 Hormonal Assessments
For hormonal assessment fasting blood samples were taken at screening, mainly between 9:00 and 11:00 AM to control for circadian influence on hormone levels. In both men and women, 17β-estradiol was assessed using 5mL separator tubes. The lowest measurable value of estradiol was 40 pmol/L. Participants with an 17β-estradiol serum level lower than 40 were considered to have an 17β-estradiol level of 40 in data analysis. Also, due to measurement errors, in some patients the assessment of 17β-estradiol only determined whether serum 17β-estradiol levels were lower than specific thresholds: <120 pmol/L or <200 pmol/L, after which these participants were excluded from the current study, since the actual 17β-estradiol serum levels cannot be predicted accurately enough. Free testosterone was assessed in men only in pmol/L. The reference values of the assays according to the diagnostic department of the UMC Utrecht were: free testosterone in men, 230-600 pmol/l; estradiol in men <50 years, 40-150 pmol/l; 17β-estradiol in men >50 years, 70-200 pmol/l; estradiol in perimenopausal women, 180-2,000 pmol/l; estradiol in postmenopausal women, 10-50 pmol/l.
2.4 Statistical analyses
Table 1. Description of dependent variables
Verbal Memory z-score Total number of recalled words during list learning, measured in terms of standard deviations from the mean score in healthy subjects, adjusted for age and sex
Verbal Fluency z-score Total number of generated unique words within a category, measured in terms of standard deviations from the mean score in healthy subjects, adjusted for age and sex
D-level Average level of syntactic complexity per sentence
Speech rate Average number of produced syllables per speech time in seconds
All statistical analyses were performed using R Version 3.6.1. (2019) and RStudio Version 1.2.5019 (2019), and figures were produced using the package ggplot2 (Wickham, 2009). For descriptive statistics, continuous variables were reported as mean ± standard deviation (M ± SD). Outliers were detected and removed using the interquartile range (IQR) criterium and boxplots. All analyses were run separately for female and male participants, because of sex-specific reference ranges of estrogen and testosterone levels. To test for normality of the variables the Shapiro-Wilk test was used. Pearson’s correlation test and linear regression analyses were used to determine the relationship between serum hormone levels and verbal performance, in which 17-beta-estradiol and free testosterone were used as predictive (independent) variables, and verbal memory, verbal fluency, syntactic complexity and speech rate were used as dependent variables. For verbal memory and fluency, we used standardized z-scores adjusted for age and sex as dependent variables: a z-score of 0 indicates a value equal to the mean, with a z-score of 1 the value is one SD higher than the mean (Keefe et al., 2008). For syntactic complexity, we used average D-level per sentence, and for speech rate we used average number of syllables per second. (See table 1.) Additionally, multivariate regression analyses were performed for the same variables adjusting for years of education. Statistical significance was defined as p < 0.05.
3. Results
3.1 ParticipantsDescriptive statistics of the sample are presented in table 2. From all 110 participants that enrolled in the RAPSODI study, sixteen participants were excluded from the dataset for the current study. Five male participants and one female participant were excluded because they did not complete the BACS or the interview, eight female participants were excluded from whom an estradiol threshold of <120 or <200 pmol/L was measured, two female participants were excluded because of outlying estradiol levels. This resulted in 94 participants, of which 73 were male. Dependent and predictive variables were all normally distributed except for estradiol levels. The 17β-estradiol serum levels in both male and female samples were not normally distributed and were therefore log-transformed for analyses.
Table 2. Summary of demographics and descriptive statistics
Characteristic Total Males Females
N = 94 N = 73 N = 21
Education Level (in years) 12.0 ± 2.6 12.2 ± 2.5 11.4 ± 2.7
Age at onset of disease 24.3 ± 8.6 24.1 ± 7.6 26.0 ± 11.6
BMI, kg/m^2 27.2 ± 4.7 27.0 ± 4.7 27.8 ± 5.1
Baseline PANSS score
Positive symptoms 15.4 ± 4.8 15.6 ± 4.8 14.8 ± 4.9 Negative symptoms 13.6 ± 5.0 13.8 ± 5.4 12.5 ± 3.1 General symptoms 29.9 ± 7.9 29.5 ± 7.4 31.0 ± 7.8 Total score 14.5 ± 13.8 58.9 ± 14.8 58.3 ± 13.7 Verbal performance BACS Verbal Memory (Z) -1.0 ± 1.1 -0.86 ± 1.0 -1.6 ± 1.3 Verbal Fluency (Z) -0.86 ±1.2 -0.82 ± 1.2 -0.96 ± 1.16 Speech production D-level 1.87 ± 0.69 2.0 ± 0.7 1.3 ± 0.2 Speech rate 2.66 ± 1.1 2.3 ± 0.5 2.3 ± 0.4
Hormone serum levels
17β-oestradiol (pmol/L) 104.6 ± 61.7 100.5 ± 36.1 97.7 ± 63.2
Free testosterone (pmol/L) - 301.3 ± 97.1 -
Data are presented as mean ± SD, unless otherwise noted. Abbreviations: BMI, Body Mass Index; PANSS, Positive and Negative Syndrome Scale; BACS, Brief Assessment of Cognition in Schizophrenia; Z, z-score; D-level, Development Level (syntactic complexity).
3.2 Results male SSD patients
According to the Pearson correlation test and multiple regression analysis on the relationship between free testosterone and verbal
cognitive performance in men, there were no statistically significant correlations between serum free testosterone and any of the verbal cognitive performance variables (Table 3). Subsequently, the second multiple regression model on the effect of estradiol and free testosterone on verbal cognitive performance in men, while adjusting for education level in years (Table 4). There was a statistically significant effect (P = .039) of free testosterone on verbal memory z-score when adjusting for years of education.
Both non-adjusted and adjusted models showed negative beta-components for the effect of log-17β-estradiol on verbal memory, verbal fluency and D-level.
3.3 Results female SSD patients Figure 1. Correlation between
log-17β-estradiol and speech rate (nsyll/sec) in female SSD patients
In females, serum estradiol levels showed a significant inversed correlation with speech rate in female SSD patients (R= -0.55, P = .035), as shown in Figure 1. Moreover, serum estradiol levels were not significantly correlated with verbal memory and verbal fluency z-scores, and D-level (Table 5). When adjusting for years of education with multiple regression analysis, estradiol did not show a significant effect on any of the dependent variables, including speech rate (P > 0.05) (Table 6).
Table 3. The effect of 17β-oestradiol and free testosterone serum levels on cognitive verbal performance in male SSD patients.
17β-estradiol Free Testosterone
Dependent variable R β F R2 p R β F R2 p
BACS (n = 65) BACS (n=58)
Verbal Memory (Z) -0.067 -0.19 0.29 0.0045 0.59 Verbal Memory (Z) 0.24 0.0024 3.306 0.056 0.074
Verbal Fluency (Z) -0.198 -0.68 2.58 0.039 0.11 Verbal Fluency (Z) 0.14 0.0016 1.192 0.021 0.28
Speech production Speech production
D-level (n= 29) -0.041 0.077 0.046 0.002 0.83 D-level (n=34) 0.0047 <0.001 0.007 <0.001 0.98
Speech rate (n = 34) 0.042 0.057 0.057 0.002 0.81 Speech rate (n=39) 0.086 <0.001 0.2765 0.0074 0.60
*Significant at p < 0.05, analyzed by Pearson rho correlation (R) and linear regression. Abbreviations: BACS, Brief Assessment of Cognition in
Schizophrenia; D-level, Development Level; PANSS, Positive And Negative Symptom Scale. log transformed 17β -oestradiol was used in correlation and regression analyses.
Table 4. The effect of log-17β-oestradiol and free testosterone serum levels on cognitive verbal performance in male SSD patients,
adjusted for years of education.
17β-Estradiol - adjusted for Years of Education
Free Testosterone - adjusted for Years of Education
Dependent variable: β F R2 p β F R2 p
BACS (n=65) BACS (n=58)
Verbal Memory (Z) -0.1496 0.72 0.023 0.68 Verbal Memory (Z) 0.003 2.56 0.085 0.039*
Verbal Fluency (Z) -0.453 1.53 0.0477 0.304 Verbal Fluency (Z) 0.002 0.98 0.034 0.205
Speech production Speech production
D-level (n=29) -0.079 0.035 0.0027 0.832 D-level (n=34) <0.001 0.071 <0.001 0.949
Speech rate (n=34) 0.054 0.059 0.0039 0.831 Speech rate (n=39) 0.002 0.981 0.03445 0.205
*Significant at p < 0.05; results of multiple regression analysis, adjusting for years of education. Log-transformed b17-oestradiol was used in correlation and regression analyses. Abbreviations: BACS, Brief Assessment of Cognition in Schizophrenia; D-level, Development Level; PANSS, Positive And Negative Symptom Scale.
Table 5. The effect of 17β-oestradiol and free testosterone serum levels on cognitive verbal performance in female SSD patients. 17β-estradiol (nmol/L)
R β F-statistic R2 p
BACS (n = 20)
Verbal Memory (Z) -0.26 -0.590 1.339 0.069 0.26
Verbal Fluency (Z) 0.004 0.008 0.0003 1.71E-05 0.99
Speech production
D-level (n= 7) -0.20 -0.076 0.214 0.040 0.67
Speech rate (n = 8) -0.55 -0.555 7.357 0.551 0.035*
*Significant at p < 0.05, analyzed by Pearson rho correlation (R) and linear regression. Abbreviations: BACS, Brief Assessment of Cognition in
Schizophrenia; D-level, Development Level; PANSS, Positive And Negative Symptom Scale. log transformed 17β -oestradiol was used in correlation and regression analyses.
Table 6. The effect of 17β-oestradiol and free testosterone serum levels on cognitive verbal performance in female SSD patients,
adjusted for years of education.
17β-estradiol (nmol/L)
β F-statistic R2 p
BACS (n=20)
Verbal Memory (Z) -0.55683 3.836 0.311 0.235
Verbal Fluency (Z) 0.02568 0.773 8.34E-02 0.956
Speech production
D-level (n=7) -0.05192 0.100 0.0478 0.831
Speech rate (n=8) -0.53826 3.081 0.552 0.096
Significant at p < 0.05; results of multiple regression analysis, adjusting for years of education. Log-transformed b17-oestradiol was used in correlation and regression analyses. Abbreviations: BACS, Brief Assessment of Cognition in Schizophrenia; D-level, Development Level; PANSS, Positive And Negative Symptom Scale.
4. Discussion
Cognitive and language impairments are widely observed in SSD patients and have a great impact on patient’s everyday life. Additionally, sex differences in the occurrence and severity of these impairments indicate an influence of sex hormones in SSD patients. Currently, much research has been done on the role of sex hormones, especially estrogen, on symptomatology in SSD patients. However, the relationship between sex hormones and cognitive verbal/ language performance has been much less extensively researched. Therefore, the aim of this study was to investigate the effect of estrogen and testosterone on cognitive and verbal performance in patients with a schizophrenia spectrum disorder.
The results on the effect of serum estrogen levels on cognitive verbal performance in men were not in line with our hypotheses, nor were the results on the effect of serum testosterone levels on cognitive verbal performance in men. Also, the expected effect of serum estrogen levels on cognitive verbal performance in women could not be confirmed. However, when adjusting for years of education, we found a significant positive effect of serum testosterone levels on verbal memory performance in men. Interestingly, the effect of years of education as a covariable made the effect of serum testosterone levels on verbal memory performance more significant. This result is in line with a prior study, that showed serum testosterone levels and years of education to be significant predictors of performance in multiple cognitive domains, including
verbal memory, in SSD patients (Moore et al., 2013). Additionally, this study did not find testosterone as a significant predictor for verbal fluency, even when adjusting for years of education.
Moreover, we found that estrogen was significantly and inversely correlated with speech rate in female SSD patients. According to prior research on language disorders, speech rate can indicate fluency of speech (e.g. Covington et al., 2005; De Jong & Wempe, 2009;
Kormos & Denes, 2004). However, verbal fluency scores in females did not show the same inversed correlation with estrogen levels. This might be due to the greater deficit of semantic fluency to phonemic fluency in SSD patients (Henry & Crawford, 2010). For further research, it might be interesting to look at the effect of estrogen on both semantic and phonemic fluency separately. Additionally, although we found serum
estradiol levels to be a significant predictor of speech rate in women, this result was obtained from only 8 participants which should be taken into account when interpreting this result. Further research with a larger female study population could elucidate if estradiol is significantly related to speech rate.
Furthermore, our results on the effect of estrogen in female SSD patients do not coincide with several prior studies, in which estrogen is often found to have a protective effect on symptom severity. For instance, Hoff et al. (2001) showed that estradiol levels in female SSD patients are positively correlated with cognitive performance in language and verbal memory. Also, studies that investigated the effect of estrogen augmentation and hormone replacement therapy (HRT) in postmenopausal SSD patients, showed a positive effect of on negative and cognitive symptoms (Lindamer, Buse, Lohr, & Jeste; Heringa, Begemann, Goverde, & Sommer). In contrast to this, Bergemann et al. (2008) showed that estrogen intake in SSD females did improve metaphoric speech performance but did not improve verbal ability and word fluency. Additionally, Thompson et al. (2004) found that estrogen levels in female SSD patients do not affect verbal and articulatory performance. The results of the current study coincide with these last to studies. These inconsistent findings over previous and current research on the effect of estrogen on cognitive and verbal domains, may be caused by different methods for the assessment of cognitive functioning and language production. To elucidate the relationship between sex hormone levels, cognition and verbal performance, further research on this matter must be conducted.
In our study, we did not find any correlations between estrogen and cognitive or verbal performance in male SSD patients. In contrast, the expression of estrogen receptors in both male and female SSD patients is decreased (Weickert et al. 2008; Perlman et al., 2005). Also, there is evidence that estrogen therapy positively affects psychotic symptoms and cognitive impairment in males (Kulkarni et al., 2013). Other than these studies, the relationship between estrogen and cognitive and verbal functioning is not as extensively researched in men as in women with SSD. Therefore, our findings might substantiate the difference in the effect of estrogen between men and women with SSD.
There are some limitations to this study. First of all, there was a sampling bias in the current study, since all participating SSD patients were to be stable. Therefore, this sample might not represent more severe cases of SSD. However, the PANSS interview was conducted and scored to assess severity of symptoms, which indicated that participants were indeed impaired on schizophrenia characterizing domains. Also, the sample of participating females was rather small, which must be taken into account when looking at the results of the study. Future research with a larger sample might substantiate a better understanding and representation of the effect of estrogen in female SSD patients.
Furthermore, using years of education as an adjustment in SSD might be seen as a ‘matching fallacy’ (Meehl, 1970), since years of education might not coincide with underlying abilities and intellectual aspects as in healthy subjects, since SSD patients might never complete their potential education level due to the disease (Hakulinen et al., 2019). However, the results of this study shows that the SSD patients that
enrolled in this study were all somewhat stable, and had average age at onset of the disease of 24.3 ± 8.6 years, indicating that they might have attained this potential education level.
In the future, it might be interesting to look at the interaction of the sex hormones that are analyzed. For instance, the hormone prolactin can suppress the production of estrogen and testosterone, thus it might be interesting for future research to additionally investigate the effect of prolactin on the verbal and cognitive performance. Also, testosterone can be converted to estrogen in men (Schulster et al., 2016), therefore it might be interesting to look at the estrogen-testosterone ratio in future research on the effect of sex hormones in SSD patients. Lastly, since computerized automatic language analyzation, as was used in the current study to assess syntactic complexity and speech rate, is a relatively new technique to assess language performance in SSD patients, it is important that similar studies will be conducted.
In this study, we found no significant linear relationships between sex hormones estrogen and testosterone, and cognitive or verbal performance in male and female SSD patients. We did find a significant effect of testosterone on verbal memory performance in males, when adjusting for years of education. These findings implicate that further research needs to be conducted on the effect of estrogen in men and women with SSD. Also, these results question the protective role of estradiol in male SSD patients. The way in which sex hormones relate to different symptoms of schizophrenia is an interesting, but complex matter and requires further investigation.
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