Front. Psychol., 12 July 2016
Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow-release GnRHa (triptorelin acetate—Decapeptyl SR® 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the children’s parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohen’s d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohen’s d = 1.03); lower heart rate was associated with longer treatment duration (r = −0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health.
Introduction
Central precocious puberty (CPP) is defined as the advent of an otherwise normal puberty before the age of 8 years in girls and 9 years in boys due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis (Nebesio and Eugster, 2007). The etiology of CPP is unclear and varies with gender. It is predominantly found in girls and while the majority of female CPP is idiopathic, in boys it is more frequently secondary to an organic cause (e.g., tumor; Choi et al., 2013). CPP incidence is age dependent. Danish data from 1993 to 2001 showed an incidence of 8:10,000 in girls aged 5–9 and 1–2:10,000 in boys aged 8–10 (Teilmann et al., 2005).
CPP is associated with early bone maturation and reduced adult height in the youngest cases. Pharmacological blockade of the gonadotropin stimulus with GnRH analogs (GnRHa), which leads to cessation of gonadal sex hormones production, is nowadays considered the standard treatment for CPP (Carel et al., 2009); the main treatment goals are an increase in adult height and prevention of psychological problems (Sonis et al., 1985; Johansson and Ritzen, 2005; Tremblay and Frigon, 2005). While research shows that treatment can positively influence adult height in treated girls, especially if started before 6 years of age (Carel et al., 2009), the effects in boys and with regard to psychological functioning are less explored. Both a recent consensus statement and an update on the usage of GnRHa in CPP strongly emphasize the need for more research regarding GnRHa effects on psychological functioning (Carel et al., 2009; Chen and Eugster, 2015).
GnRHa treatment can potentially influence CPP children’s psychological functioning through several pathways. Firstly, postponement of the pubertal development by blockade of sex hormones production can reduce psychological distress associated with early biological maturation. Secondly, abolition of sex hormone influences on the developing brain may on its own have an effect on cognitive development. Finally, GnRHa can potentially influence cognitive development via GnRH receptors that are widely present in brain areas not related to reproduction (Skinner et al., 2009). Several human and animal studies suggest that GnRHa may indeed influence cognitive functioning. A decline in working and episodic verbal memory associated with GnRHa treatment has been observed in women with benign leiomyomata uteri and endometriosis (Grigorova et al., 2006; Craig et al., 2007). In an animal study, using an ovine model of pubertal development, prepubertal GnRHa treatment significantly affected emotion regulation capacity, reward seeking behavior, and emotional reactivity in young sheep (Wojniusz et al., 2011; Evans et al., 2012). Furthermore, GnRHa treatment significantly and sex-specifically affected hippocampus and amygdala gene expressions and altered amygdalae volumes in the same animals (Nuruddin et al., 2013a,b,c). In addition, possible effects of GnRHa on cardiac health have recently been postulated, following findings of increased prevalence of cardiovascular disease in prostate cancer patients treated with GnRHa (Tsai et al., 2007; Keating et al., 2010).
The consensus statements and findings from adult and animal studies warrant a broader investigation of cognitive and emotional functioning in GnRHa treated CPP children. In the current study we, therefore, compared CPP girls under GnRHa treatment to age-matched controls. We assessed children’s cognitive function by using a comprehensive neuropsychological test battery consisting of paper and pencil and computerized tests. Additionally, we assessed cognitive, social, and behavioral function at home and school situations by employing questionnaires completed by the children’s parents. Since animal twin studies indicated poorer emotional regulation capacity and higher emotional reactivity in GnRHa treated lambs compared to their untreated twins (Wojniusz et al., 2011; Evans et al., 2012), assessment of emotional processing was additionally included in the study. We employed the emotional flanker task (EFT) for the assessment of emotional reactivity (Bishop et al., 2004) and calculated vagally mediated heart rate variability (HRV) as a measure of emotional regulation capacity (Appelhans and Luecken, 2006; Thayer and Lane, 2009; Koval et al., 2013).
Materials and Methods
Participants
Clinical records of girls with idiopathic CPP, treated with GnRHa between November 2009 and December 2011, either at the University Hospital Ghent or the University Hospital Brussels, were reviewed. CPP was defined according to the combination of the following three items: (a) the onset of breast development before the age of 8 years; (b) accelerated growth velocity in the months before diagnosis; and (c) advancement of bone age by at least one year compared to chronological age. In cases with uncertain diagnosis, a standardized LHRH test (applied in 12 out of 15 girls) yielding an LH peak above 4.5 U/l and the finding of an estrogenized uterus (corpus length/cervix length > 1) on pelvic ultrasound were considered as additional evidence for the presence of CPP. A minimum age of 9 years (due to the complexity of the test package), treatment by GnRHa for at least 6 months, and 2–3 monthly clinical follow-up was mandatory to enter the study.
GnRHa treatment was adjusted in case of incomplete pubertal suppression as judged by physical examination and LH/FSH blood sampling or repeated GnRH testing. At the time of the study, puberty suppression was determined clinically and radiologically as successful in all patients based on Tanner stage (no progression of breast development), growth velocity (decreased as compared to pre-treatment), and bone age. Exclusion criteria were additional endocrine or other chronic diseases, which could influence cognitive and behavioral function; learning difficulties, defined as an IQ < 70; and non-European descent due to race/ethnicity based differences concerning age of pubertal onset (Biro et al., 2013). On the basis of these criteria, two girls out of 17 were excluded. Fifteen healthy controls, carefully matched for age, were recruited through flyers distributed in public places. All patients and controls gave their assent, and parents gave written informed consent. The study was approved by the ethical committees of both institutions; Commissie Medische Ethiek UZ Gent and Commissie Medische Ethiek UZ Brussel.
Procedures
Patients and controls were invited to either the University Hospital Ghent or Brussels. After assessment of medical history and physical examination including anthropometrics and pubertal staging by an experienced pediatric endocrinologist, bone age was assessed from an X-ray of the left hand and wrist by one single investigator (MC) according to the Greulich and Pyle method. All CPP patients and controls underwent neuropsychological assessments, an emotional reactivity test, and heart rate monitoring for calculation of HRV. Behavioral questionnaires were completed by parents. All neuropsychological tests were applied by one single psychologist (NC), experienced in pediatric clinical psychology, and trained in test administration and scoring, and consisted of a range of cognitive, behavioral, and neuropsychological assessments. Heart rate monitoring, EFT and computer based cognitive tests (CANTAB) were supervised by the same investigator (SW) in all participants. In total, tests took ~2.5 h to complete. The girls were offered two breaks and soft drinks in between the testing blocks and a small financial compensation for participation in the study.
Neuropsychological Tests and Questionnaires
Intellectual Level
An abbreviated version of the Wechsler Intelligence Scale for Children-III (WISC-III) was used to generate an estimate of general cognitive ability. Two verbal (Vocabulary and Information) and two performance subtests (Block Design and Picture Completion) were used. This short-form combination has been shown to have a high reliability (Atkinson and Yoshida, 1989).
Memory Tests
The Rey Auditory Verbal Learning Test [RAVLT; Dutch version: (Saan and Deelman, 1986)] was used to evaluate auditory-verbal memory. The recognition component was not assessed in this study. We derived five scores: Immediate Memory, Best Memory, Proactive Interference, Retroactive Interference, and Delayed Recall. We also computed two combined scores which are frequently used in studies that employ RAVLT: Learning Rate, reflecting the learning ability of the subject, and Total Learning, representing the capacity to recall and accumulate words across learning trials.
The Continuous Visual Memory Test (CVMT; Trahan and Larrabee, 1988) measures visual learning and memory, i.e., acquisition of information and retention over time (storage and retrieval). Acquisition or short-term memory included Immediate Memory and Proactive Interference scores, as well as Learning Rate score. Storage includes the CVMT Recognition score. Retrieval from long-term storage included Delayed Recall, Retroactive Interference, Best Learning, and Total Learning scores on both the RAVLT and CVMT.
Spatial Ability
The Mental Rotation Test in which the subject was asked to compare two 3D objects and state if they are the same images (non-mirror or mirror images) was an adapted version of the task used by Hugdahl et al. (2006), originally developed by Shepard and Metzler (1971). The test had 20 pairs of images, the subjects were judged on how accurately, and rapidly they could distinguish between the pairs. The task has not been specifically validated for use in children, however in our sample the children performed similarly to what has been observed in adults.
Executive Function and Attention
A selection of four tests from the Delis-Kaplan Executive Function System (Delis et al., 2001) was used to assess different aspects of executive functions; the Trail Making Test, the Verbal Fluency Test, the Color Word Interference Test, and the Design Fluency Test. Composite executive functioning and processing speed domain scores are expressed as mean of subscale z-scores.
Additionally a selection of four tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), provided by Cambridge Cognition Ltd. was used to further assess executive function and attention. CANTAB tests are computerized, giving higher chance to discover minor differences between the groups. Although CANTAB tests were originally developed to assess patterns of cognitive decline in adults, their applicability for usage in children in age group 5–12 has been previously confirmed (Luciana and Nelson, 2002). The following tests were included:
Choice reaction time (CRT) is a 2-choice reaction time test with stimulus and response uncertainty introduced by having two possible stimuli (left and right arrows) and two possible responses (left and right buttons). Mean correct response latency and percentage of correct responses were recorded as outcome measures.
Match to sample visual search (MTS) is a matching test, with a speed/accuracy trade-off. The subject is presented with a sample-stimulus figure, composed of four colored elements displayed in the middle of the screen. After a brief delay, a varying number of similar patterns (1, 2, 4, or 8) are shown around the edge of the screen with only one of them matching the sample-stimulus pattern. The subject has to touch the matching pattern as fast as possible on the screen. Mean correct response time and percentage of correct responses were used as outcome measures.
Spatial working memory (SWM) tests subject’s ability to retain spatial information and to manipulate remembered items in working memory. A number of colored boxes are shown on the screen. By process of elimination, the subject should find one blue “token” in each of a number of boxes. The number of boxes is gradually increased from three to eight boxes and the color and position of the boxes are changed from trial to trial to discourage the use of stereotyped search strategies. Total number of errors and SWM Search Strategy were used as outcome measures.
Stop signal task (SST) is a response inhibition test, giving a measure of an individual’s ability to inhibit a pre-potent response. The subject is told to press the button that corresponds to the direction of the arrow presented on the computer screen, but, if they hear an auditory signal, they should withhold their response. There are five assessed blocks, each of 64 trials. The last four blocks were subjected to statistical analysis. The main outcome measure was the Stop Signal Response Time (SSRT), which is an estimate of the latency of the stop process. Additionally, the probability of inhibiting the response when signal occurred was calculated.
Parental Questionnaires
The Behavior Rating Inventory of Executive Function (BRIEF)—the parent version (Dutch translation Smidts and Huizinga, 2009) assesses children’s cognitive and behavioral aspects of executive function in home situations. It includes eight non-overlapping clinical scales (Inhibit, Initiate, Organization of Materials, Shift, Working Memory, Monitor, Emotional Control, Plan/Organize) and two validity scales (Negativity and Inconsistency of responses)
The Child Behavior Check List—4–18 years (Dutch translation: Verhulst and Van der Ende, 2004) is a standardized measure of academic, social competence, and behavioral problems. The questionnaire is completed by parents and includes eight sub-scales: Withdrawn, Somatic complaints, Anxious/Depressed, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, and Aggressive Behavior. The first three subscales add up to the Internalizing Problems scale and the last two to the Externalizing Problems scale. Finally, the overall Total Problems scale consists of all items. Additionally a Social Competence scale is derived from items grouped into Activities, Social, and School constructs. For each scale, T-scores (mean = 50 ± 10) can be obtained. A clinical cut-off point on the Total, the Internalizing and the Externalizing score was set at T = 60.
Socioeconomic Indicators
Two socioeconomic indicators for parental occupations were used. An occupational class was constructed on the basis of International Standard Classification of Occupations (ISCO-08) (ILO, 1990) namely (1) managers and professionals; (2) technicians, clerks, and service workers; and (3) craft workers, machine operators, and elementary occupations. The number of years of formal education was divided into three groups: Secondary school, Higher education Short Type, and Higher Education Long Type or University.
Emotion Processing
The Emotional Flanker Task (EFT)
EFT was used to assess emotional reactivity. The task is an adapted version based on previous studies (Bishop et al., 2004). With an inter-trial interval of 1000 ms, on each trial, two faces and two houses were presented in horizontal and vertical pairs, respectively (Figure 1). Participants were instructed to decide as fast as possible whether the presented buildings were identical or not, and to respond by pressing a corresponding response button. They were informed that the faces presented in the periphery were irrelevant and didn’t need to be attended to. If a participant did not make a choice within the first 4 s, the next trial was automatically presented. After five practice trials, participants were exposed to 207 trials, starting with three consecutive trials with neutral flankers to increase the effects of emotional flankers (Bishop et al., 2004). Out of the remaining 204 trials, target stimuli (houses) were identical in 50% of the trials; in 35% of all presentation trials flanker stimuli consisted of anxious faces, and in 65% of trials of faces with neutral expressions. The lower proportion of emotional flankers was chosen to increase the stimulus valence and resulting reactivity to these trials (Bishop et al., 2004).
Figure 1
Figure 1. Emotional flanker task. In 207 trials, children were requested to decide as fast as possible whether two houses were identical or not. The faces were irrelevant for task solution and did not need to be attended to. The difference between reaction times in the presence of anxious and neutral faces (flanker valence effect) was used as a measure of emotional reactivity. Pictures of facial expressions were obtained from the Karolinska Directed Emotional Faces database (Lundqvist et al., 1998).
The main outcome measure was a flanker-valence effect (FVE), which was calculated by subtraction of reaction times in the valence condition “neutral” from valence condition “anxious.” Larger reaction time differences between distractor valences “neutral” and “anxious” were interpreted as higher emotional reactivity (Grose-Fifer et al., 2013). To avoid confounding biases caused by different processing of identical and non-identical target stimuli, behavioral analyses were done separately for both conditions. Only correct responses were analyzed.
Heart Rate and Heart Rate Variability (HRV)
HRV has been extensively used in psychophysiological research to assess emotion regulation capacity (Thayer et al., 2012). Heart rate (HR) and HRV were calculated from the inter-beat intervals (IBIs), recorded with a sampling rate of 1000 Hz, using the Polar RS800® monitor. After a Polar belt was placed around the participant’s chest, she was seated in a comfortable chair and asked to relax for 10 min (baseline). Thereafter, she was led over to a computer station and performed the EFT. The recording was stopped after task completion. Altogether, 20 min IBI-recordings of 29 out of 30 participants were collected. IBI recordings of one CPP girl were invalid due to equipment failure. Prior to analysis, all recordings were cleared of artifacts using ARTiiFACT software (Kaufmann et al., 2011). A minimum requirement of 95% of artifact-free IBIs was set as an inclusion criterion. No participant exceeded the 5% artifact-threshold; however there was a significantly higher mean number of artifacts in the treatment group (M = 7.1, SD = 4.4) vs. controls [M = 2.3, SD = 3.6; t(27) = 3.2, p = 0.003]. Five minute-periods of data from the baseline and the EFT conditions, respectively, were chosen for further analyses, according to the Task Force (1996) guidelines (1996). HR and Root Mean Square of Successive IBIs (RMSSD) were analyzed as time domain measures. Additionally, power spectral density of High (HF), frequency was analyzed using Fast Fourier transformation following guidelines of the Task Force (1996). Frequency spectrum data were normalized by logarithmic transformation. Recordings from baseline and during EFT were analyzed separately.
Statistical Analysis
SPSS (version 20) was used for statistical analyses. Due to a relatively low number of participants, resampling of data, applying bias-corrected and accelerated bootstrapping technique (5000 resamples) was used to control for data stability. For comparisons between the groups, independent sample t-tests were applied, while a paired sample t-test was used to assess the differences between repeated measurements. If differences between groups were significant, Cohen’s d was calculated for effect size estimation. Partial correlations were used to explore the associations between treatment duration and cardiac measures and behavioral test while controlling for chronological age. Group differences in socioeconomic status were assessed by comparing the educational levels of children’s parents using Fisher’s exact test.
Results
The clinical characteristics of CPP girls and controls are summarized in Table 1. Eleven out of 15 girls had started treatment with 11.25 mg intramuscular injection of GnRHa (Decapeptyl SR®) every 10th week, and 4 out of 15 girls with a 3.75 mg injection every 4th week. Patients were monitored regularly and their medication was adjusted in case of incomplete pubertal suppression as judged by physical examination and LH/FSH blood sampling or repeated GnRH testing; 11.25 mg every 8 weeks in three girls, 11.25 mg every 6 weeks in one girl, 11.25 mg every 10 weeks in two girls (from 3.75/per 4 weeks), and 11.25 mg every 12 weeks in one girl. At study entry (T1), 14 out of 15 girls had a Tanner score for breast development equal to or less than at the start of the treatment. Median duration of GnRHa treatment was 28 months (range: 8–57) at the time of the study. As expected, body height, BMI and bone age were still higher in treated CPP girls as compared to controls. Over the course of treatment, the difference between bone age (BA) and chronological age (CA) was reduced by 8.6 months, [t(14) = 2.2, p = 0.042]. Whereas all control girls were healthy, one CPP girl suffered from chronic otitis media and one from hip dysplasia, independently of the CPP and GnRHa treatment….
CONSIDERATIONS
Commentary: Cognitive, Emotional, and Psychosocial Functioning of Girls Treated with Pharmacological Puberty Blockage for Idiopathic Central Precocious Puberty
