Precocious puberty, a condition in which sexual and physical development starts unusually early in childhood, is typically defined as the onset of puberty before age 8 in girls and before age 9 in boys . Often there is no clear cause for precocious puberty. The most common form is central precocious puberty (CPP), with activation of the hypothalamic-pituitary-gonadal axis, but precocious puberty may also result from disorders of the ovaries, testicles or adrenal glands; tumor of the hypothalamus; or tumors that release the hormone human chorionic gonadotropin.
Precocious puberty is rare, affecting approximately 1 in 500 girls and 1 in 2000 boys . Girls are more frequently affected by CPP than boys, with a male to female ratio of CPP occurrence of at least 1:10 . Because growth is slowed after puberty, there is concern that children with precocious puberty will not attain their adult height potential. Furthermore, research suggests that early puberty may result in psychological and social problems for children, including greater likelihood of depression, aggressiveness, behavior problems, social withdrawal, sleeping problems, obsessive behavior and psychological stress , , , with negative implications on quality of life. Girls with precocious puberty may experience lower self-esteem, poorer coping skills, higher school absenteeism, and greater likelihood of substance abuse disorders and attempted suicide than girls who do not experience early pubertal development .
There are few well-designed studies on the psychosocial impacts of precocious puberty, specifically CPP. The objective of this study was to identify key psychosocial and health-related quality of life (HRQOL) impacts of CPP and to evaluate the existing patient-centered outcome assessments (including patient-reported, parent-reported or observer-reported measures) that have been used or may be relevant for use in children aged 2–12 years with CPP.
Materials and methods
Relevant articles were identified for review through searches of the PubMed/MEDLINE database, Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, ClinicalTrials.gov, the Physician’s Desk Reference Digital Drug Database , and websites for the US Food and Drug Administration (FDA) and the European Medicines Agency. The searches were limited to English-language publications describing research in humans.
The studies identified in the literature review were screened using prespecified inclusion and exclusion criteria (see Table S-1 in the Supplemental Material). The literature review included studies in populations with a broader age range of puberty onset than the current definition of CPP. Studies were included unless the subjects were categorized as experiencing normal puberty (beginning at or after age 10 for girls or age 11 for boys). Figure 1 presents the number of abstracts and full-text articles reviewed and reasons for exclusion during successive rounds of review. Of the 468 studies identified, 49 full-text studies were reviewed, and 15 studies were identified for inclusion.
The selection of instruments for in-depth review was based on a number of factors, including use of the measure in the CPP literature, the relevance of the concept(s) assessed and whether the measure was developed for use with children. The goal of these searches was to identify publications describing the development, validation or use of an outcome assessment of interest in children with CPP. The in-depth instrument review evaluated the objectives, administration format (e.g. self-report, proxy-report or interview-administered), recall period, number of items and subscales, development, measurement properties and relevance of each instrument. Among the outcome assessments identified in the review of the published literature, the CBCL and PedsQL were selected for the detailed instrument review based on use in pubertal studies and relevance of the issues assessed. In addition to the instruments identified in the literature review, the Children’s Health Questionnaire (CHQ) and the SF-10 Health Survey for Children were reviewed because of their widespread use and expected relevance in assessing concepts of interest in CPP.
This review study did not directly involve human participants; thus, informed consent procedures were not applicable.
Patient-centered concepts in central precocious puberty
Among the identified studies of precocious puberty or early pubertal maturation, the most frequently assessed concepts were depression/depressive symptoms and anxiety, behavior and behavioral problems, body image and self-esteem and personality type/characteristics. Other concepts explored less frequently but nonetheless relevant included HRQOL, psychosocial adjustment and stress. Table S-2 in the Supplemental Material summarizes the identified patient-centered concepts, references, study population and country.
Qualitative research on the subjective experience of central precocious puberty
Baumann and colleagues  described a study of 19 Swiss girls mean onset of puberty at 4½ years, treated with gonadotropin-releasing hormone (GnRH) agonists. Participants reported feelings of shame and insecurity, “mostly because of tallness and breast development”; 47.4% “often” or “always” felt older or more mature than peers, and 47.4% were subjected to remarks about their sexual characteristics from peers “sometimes” or “often”. Most (84.2%) reacted with frequent or occasional withdrawal. The authors suggested that precocious puberty was a source of stress and insecurity for young patients .
Xhrouet-Heinrichs and colleagues  reported a longitudinal Belgian study of 20 girls with CPP (15 treated with GnRH for 2 years). Girls had breast development at 5–8 years of age. During semistructured interviews with patients, parents and their pediatric endocrinologist, conducted 1 month after diagnosis, all 20 patients expressed concerns about comments from peers regarding physical differences, primarily relating to breast development and embarrassment over pubertal differences. Most patients reported a fear of sexuality (17/20, including 12 girls from treated group) and feelings of loneliness and having no or few friends (14/20). Seven patients expressed concern about menstruation, including one girl who had already begun to menstruate, and one expressed concern about possible short adult stature. One month after diagnosis, parents of 10 patients reported that their daughters exhibited intense emotional reactions, including crying easily, shyness, and clinginess, and parents of eight patients reported that their daughters exhibited “aggressive behavior”. Twenty-four months after diagnosis, 13 of the 20 patients were still concerned about physical differences from peers. However, embarrassment about pubertal development was no longer a concern in 6 of 15 treated girls, five of whom experienced regression of breast development .
In addition to the published studies, a 2016 University of Washington Public Health master’s thesis, Identifying Areas of Needed Support for Young Girls with Central Precocious Puberty (CPP), was identified online . That study detailed 14 qualitative interviews conducted with caregivers of 16 girls aged 6–10 years with idiopathic CPP; 13 were undergoing treatment at the time of the study, two had completed treatment and one was untreated. The impacts of CPP as described by caregivers were primarily negative and included severe mood swings, irritability, and emotional outbursts affecting relationships with peers (100%) and caregivers (86%); physical changes leading to social effects or awkwardness (14%); and social effects including feeling isolated and alone (43%), being bullied (14%) and becoming a bully (6%). Communication with caregivers was negatively affected and emotionally charged (86%). For a few patients, positive psychosocial effects of CPP were identified, such as becoming a leader among peers and enjoying being taller than peers. Caregivers whose daughters were undergoing treatment (81%) or who had completed treatment (13%) noted psychosocial improvements within 1–4 weeks after treatment was initiated (31%) or more than 1 month after treatment initiation (62%).
Studies assessing patient-centered outcomes in central precocious puberty
Key studies assessing patient-centered concepts in CPP or precocious puberty are summarized in Table 1; one was interventional and nine were observational. Eight of these studies included the Child Behavior Checklist (CBCL), and only a few other outcome assessments were used. The most relevant assessments identified in the literature are described in detail in the Instrument Review section.
One single-arm interventional study evaluated 54 female patients treated with leuprolide acetate depot over 24 weeks. The CBCL Problem Behavior total score, (p = 0.0072) and Other Problems (p < 0.0001) and Sociality (p = 0.0464) subscale scores were significantly lower (i.e. improved) between baseline and week 24. However, the CBCL subscales Problem Behavior Syndrome, Anxiety/Depression, Shrinking/Depression, Somatization, Social Immaturity, Thought Problems, Attention Problems, Violation of Regulations and Offensive Behavior were not significantly different at 24 weeks .
Among the observational studies, some CBCL subscales showed significant problems in patients with CPP versus healthy controls or population norms, and whereas others found no significant differences. Significant differences in CBCL scores included Externalizing and Internalizing Problems, total Behavioral Problems and Attention Problems , , , , . Another observational study used the Children’s Social Behavior Scale – Parent Report to evaluate relational anxiety and the Revised Child Anxiety and Depression Scale – Parent Report to evaluate anxiety and depressive symptoms and found that pubertal development was significantly associated with relational aggression, anxiety and depression .
Only one of the nine studies included boys who may have had CPP . Although these children did not necessarily have a diagnosis of CPP, they participated at each follow-up (ages 6–7, 8–9 and 10–11 years), and their parents provided information about pubertal development at ages 8–9. Mensah and colleagues  compared behavior difficulties and psychosocial adjustment between children who experienced early-onset puberty (8–9 years) and those with later onset. They also examined data collected from the ages of 4–11 years to determine whether differences precede and/or continue beyond early puberty at age 8–9 years and whether differences remained after adjusting for body mass index, socioeconomic status, and ethnicity. Among girls, there was little difference in the Strengths and Difficulties Questionnaire (SDQ) total difficulties scores across age groups for those with puberty onset (as assessed by parents) at 8–9 years versus those with later onset of puberty. Boys who experienced early puberty had higher SDQ total difficulties scores at 8–9 years versus those who did not; differences were also observed earlier in childhood, at 4–5 and 6–7 years, and were maintained through ages 10–11 years. Compared with subjects who did not experience early puberty, both boys and girls who experienced early puberty had poorer Pediatric Quality of Life Inventory (PedsQL) summary scores consistently across age groups .
Instruments identified from the central precocious puberty literature (Table 2)
The CBCL is a widely used parent-, caregiver- or teacher-reported questionnaire designed to assess the competencies, adaptive functioning and behavioral/emotional problems of children aged 18 months to 18 years , . The version for children aged 1½–5 years and the version for children and adolescents aged 6–18 years are completed by parents. The CBCL contains approximately 100 problem items and 20 competence items. The items use a three-point graded response scale and varying recall periods (e.g. “now or within the past 6 months” or “now or within the past 2 months”). Items are scored as eight Syndrome scales: Aggressive Behavior, Anxious/Depressed, Attention Problems, Rule-Breaking Behavior, Social Problems, Somatic Complaints, Thought Problems, and Withdrawn/Depressed. In addition, there are four CBCL Competency scales: Activities, School, Social, and Total Competence, as well as two higher-order psychopathology scales: Internalizing and Externalizing. The CBCL appears to be content valid for assessing the competencies, functioning and behavioral/emotional problems of children and adolescents in a broad population. Items were generated in consultation with professionals and parents and modified based on the results of pilot studies , . The CBCL is widely used, and there are numerous studies documenting its psychometric properties , , , , , .
Several of the CBCL items appear potentially relevant to young children with CPP (e.g. gets teased a lot; self-conscious or easily embarrassed; Sexual problems [describe] _____; Stubborn, sullen or irritable; Sudden changes in mood or feelings; Temper tantrums or hot temper; Unhappy, sad or depressed; and Withdrawn, does not get involved with others). Moreover, the CBCL (including a Korean translation of the CBCL) has been used relatively frequently in studies of CPP – 9 times in the literature reviewed. However, the questionnaires are quite lengthy and include many irrelevant items (e.g. questions related to bathroom habits, appetite or medical symptoms). The recall periods are also very long if there is interest in assessing onset of treatment action.
The Pediatric Quality of Life Inventory version 4.0 Generic Core Scales (PedsQL) is a widely used pediatric HRQOL instrument that encompasses childhood and adolescence (2–18 years) and measures the three broad domains of HRQOL – physical, emotional and social functioning – as well as school functioning . The PedsQL comprises 23 items yielding four subscale scores: Physical Functioning (eight items), Emotional Functioning (five items), Social Functioning (five items) and School Functioning (five items); a Psychosocial Health summary score is computed from the Emotional, Social and School Functioning items. The PedsQL for children aged 2–4 years is in proxy format only; for children aged 5–18 years, the instrument is both self-report and proxy-report, with the PedsQL self-report for children aged 5–7 years being administered through interviews. Response options for patients aged 8–18 years are graded on a five-point scale. The self-report form for children aged 5–7 years has a three-point scale, with each response option anchored to a happy, neutral or sad face. In all cases, a 1-month recall period is used, and the PedsQL takes approximately 5 min to complete.
The PedsQL has demonstrated highly satisfactory reliability and validity in healthy children  and in specific pediatric populations, such as children with cancer, heart disease, diabetes and asthma , , , . The PedsQL has been shown to have satisfactory known-groups validity , , , capable of discriminating between healthy children and those with chronic illness. Although the PedsQL has had very limited use in studies of CPP, it is interesting that both boys and girls who experienced early puberty had poorer PedsQL summary scores consistently across childhood .
Additional potentially relevant instruments (Table 3)
The CHQ is a multidimensional measure of physical and psychosocial functioning and well-being , . Designed and normed for children 5–18 years of age, there is a self-report version for children and adolescents aged 10–18 years and a proxy-reported version for parents of children aged 5–18 years. The self-report CHQ includes 87 items, and the parent-reported CHQ includes 28 or 50 items, each with a 4-, 5- or 6-point ordered response scale. The recall periods vary from “the past 4 weeks” to “compared to 1 year ago”. In addition to an overall CHQ summary score, the CHQ yields physical and psychosocial subscale scores: Physical Functioning, Role/Social-Physical, General Health Perceptions, Bodily Pain, Parental Time Impact, Parental Emotional Impact, Role/Social-Emotional/Behavioral, Self-Esteem, Mental Health, General Behavior, Family Activities, Family Cohesion and Change in Health. CHQ items of potential use include questions about “argued a lot”, “had tantrums”, “felt lonely” and “acted bothered or upset”. There are also questions on the 28-item parent-reported CHQ that ask about the parent’s or family’s well-being like (“How much emotional worry or concern did each of the following cause you: your child’s physical health? your child’s emotional well-being or behavior?”).
The CHQ has been widely used and psychometrically evaluated in a wide range of patient populations. Little is known about the CHQ item development process, except that it was based on a conceptual framework. A number of studies document the satisfactory internal consistency, construct validity, and discriminating ability of the CHQ in its various forms in a number of therapeutic areas and healthy populations , , . The CHQ has not been used in studies of CPP but is of interest here because it includes a variety of concepts that appear relevant in CPP. Although the FDA prefers that patients self-report when possible, the 87-item child-report version of the CHQ is prohibitively long.
The SF-10 Health Survey for Children is a parent-completed questionnaire intended to assess the health status of children aged 5–18 years . The SF-10 is part of the Quality Metric Pediatric Health Surveys and was adapted from the CHQ. The 10 items of the SF-10 use a 4-week recall period and yield physical and psychosocial health summary scores based on the following physical and psychosocial concepts: physical functioning, role/social-physical, general health perceptions, bodily pain, role/social-emotional/behavioral, self-esteem, mental health and general behavior. There is evidence supporting the reliability, validity, and discriminating ability of the SF-10 in the general US population of children with or without a chronic condition or disability ,  but nothing regarding its responsiveness. The SF-10 is exclusively parent-reported and has not been used in studies of CPP or referenced in a product label.
The studies identified in this review demonstrate that the psychosocial and HRQOL burdens of CPP may be considerable but have not been systematically studied in many settings. In particular, qualitative research indicates that girls with CPP may experience mood swings, emotional lability and irritability, which interfere with peer and family relationships. The physical changes of puberty may cause feelings of shame, embarrassment, frustration or insecurity, as well as fear of comments from peers; these feelings may increase isolation and social withdrawal, further interfering with peer and family relationships. Early maturation (physical, cognitive, psychological) can make girls feel different from their peers and cause worry about aspects of pubertal development such as menstruation and sexuality. Although findings from interventional and observational studies have varied, several studies suggest that boys and girls with CPP experience significant social and behavior problems.
Historically, the efficacy of CPP treatment has been assessed using objective measures, with minimal reliance on patient-centered outcome assessments. In particular, the literature is lacking studies comparing results of patient-centered outcome assessments before, during and after treatment. The different treatments currently available for CPP continue to be studied, and means of assessing changes in the significant HRQOL impact of CPP in clinical trials are needed. The assessment of patient-centered outcomes in CPP is challenging, and no existing outcome assessments were identified as being entirely fit for purpose in this population. No children with CPP were involved in the development or validation of the outcome assessments identified. However, all involved the input of children and parents in item development or refinement, and all have documented evidence of reliability and validity in a variety of pediatric populations and therapeutic areas.
With children diagnosed and treated for CPP as young as 2 years of age, it is clearly not possible to have an outcome assessment that utilizes self-report exclusively at all ages. Except for the SF-10 for Children, all identified measures include a patient-reported version. The CBCL utilizes patient self-report for ages 11–18 years, with parent proxy-report for ages 1½–18 years. The PedsQL uses patient self-report for ages 5–18 years (interviewer-administered for ages 5–7 years), with parent proxy-report for ages 2–18 years. The CHQ utilizes patient self-report for ages 10–18 years, with parent proxy-report for ages 5–18 years. The CBCL and the CHQ are both excessively long questionnaires, with the patient-reported versions of these questionnaires including 100+ and 87 items, respectively. The PedsQL consists of 23 items and the SF-10 for Children consists of 10 items.
The PedsQL holds promise as a patient-centered outcome measure in CPP. As no measure has been thoroughly studied in CPP, we suggest that the 23 items of the PedsQL best encompass the concepts of psychosocial functioning appropriate to young children with CPP aged 2–12 years, with an interviewer-administered self-report version for children as young as 5 years of age. The PedsQL has also been translated into more than 70 languages, reported in hundreds of peer-reviewed journal publications, and used to support an FDA-approved labeling claim (Cuvitru for primary humoral immunodeficiency) . Because previous research in the CPP population has focused primarily on physical outcomes, use of the PedsQL and other psychosocial assessments in the CPP literature is limited. This study aimed to evaluate tools for use in future research in this area.
In conclusion, there is a lack of validated tools for measuring HRQOL in patients with CPP, which limits the ability to understand the HRQOL impact of CPP and may result in a gap in patient care. Further studies are also needed to assess whether HRQOL issues described in children with CPP improve with treatment, and whether the current trend toward earlier recognition and treatment of children with CPP improves those outcomes.
Medical writing services were provided by Kate Lothman, BA, of RTI Health Solutions. Financial support for medical-writing services was provided by AbbVie.
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The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2017-0465).
About the article
Published Online: 2018-04-12
Published in Print: 2018-05-24
Author contributions: VSL Williams: Conceptualization, Methodology, Formal analysis, Manuscript writing, Interpretation of study data. AM Soliman: Conceptualization, Funding acquisition, Manuscript writing, Interpretation of study data. AM Barrett: Methodology, Formal analysis, Manuscript writing, Interpretation of study data. KO Klein: Manuscript writing, Interpretation of study data. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study and preparation of this publication were funded by AbbVie. AbbVie participated in data analysis, interpretation of data, review, and approval of the manuscript. Kate Lothman of RTI Health Solutions provided medical writing services for the first draft of the manuscript. These services were funded by AbbVie. All authors revised the manuscript for important intellectual content.
Employment or leadership: Ahmed M. Soliman is an employee of AbbVie and owns AbbVie stocks. Valerie S.L. Williams and Amy M. Barrett are employees of RTI Health Solutions, which received research funding from AbbVie during the conduct of this study.
Honorarium: Karen O. Klein is a consultant for AbbVie but received no honoraria directly in association with this manuscript.
Competing interests: AbbVie, Inc. participated in the study design, research, data collection, analysis and interpretation, writing, review and approval of this publication.