Short summary

Worldwide, the age of pubertal onset has been declining during the last decades. The aim of this study is to establish a Danish nationwide longitudinal cohort of children with early puberty to determine the incidence of central precocious puberty (CPP) and to explore the impact of lifestyle and environmental factors on timing of puberty. It is a five-year project including all Danish children referred for precocious puberty to all 17 pediatric departments in Denmark during a 3-year period.

Rationale

Worldwide, the age of pubertal onset has been declining rapidly during the last decades. If this trend continues, extremely early pubertal onset, beginning already in the preschool years, may have yet unseen consequences for the psychosocial well-being of the child and may result in serious long-term health problems as well as societal challenges. Large epidemiological studies have shown that earlier menarche is associated with an increased risk of all-cause mortality and cardiovascular disease later in life. The factors causing earlier onset of puberty in the general population remain to be elucidated. Pubertal onset is largely determined by genetics, but genetics cannot explain the rapid shift in age at pubertal onset, hence lifestyle and environmental factors have been proposed to play a major role.

The overall objective of this study is to establish a Danish nationwide prospective cohort of children with early puberty to determine the incidence of central precocious puberty (CPP) and to explore the impact of lifestyle and environmental factors on timing of puberty.

Description of the cohort

Seventeen pediatric hospital departments in Denmark will be included and an expected more than 1,500 children referred for early puberty will be invited to participate in the study. From previous experience in cohort studies on healthy individuals, we have had a participation rate of around 30%. Since this cohort consists of patients who are going through the examinations and blood samples as part of the routine clinical work-up for CPP we expect a much higher participation rate around 70-80%. It is essential to include all departments to evaluate the incidence of precocious puberty in Denmark and to ensure power for the analyses of etiology.

Inclusion criteria: • All children (> 4 years of age) referred to one of the seventeen collaborating pediatric departments with one of the following diagnosis (ICD10) o DE301 For tidlig pubertet o DE228A Pubertas praecox centralis o DE308A Præmatur thelarche o DE270B Præmatur adrenarche o DE308 Anden hormonel forstyrrelse i puberteten o DE309 Hormonel forstyrrelse i puberteten UNS o DZ003 Kontakt mhp undersøgelse af udviklingsstatus i puberteten

Participants with cancer or chronic disease (e.g., history of malignant disease, chemotherapy or radiation or known genetic disorder) will also be included even though these diseases are known factors to affect pubertal onset. However, we want to estimate the true incidence and therefore these patients will be included.

Data and biological material

The study will include: 1. A clinical examination of the child 2. A blood sample (35 ml) 3. A urine sample (50 ml) 4. An electronic questionnaire: Background Physical activity Quality of life (KIDSCREEN-52) The clinical examination consists of height measurements (standing- and sitting-height), weight, circumference of waist and hip, body fat composition, evaluation of pubertal development, and blood pressure. The blood samples will be used for the measurement of: a) Hormones b) Bone turnover markers c) Metabolic factors d) DNA and RNA A urine sample will be collected in phthalate free containers for determination of EDCs (Parabens, phthalates, bisphenol A, UV-filters and triclosan), as well as LH, FSH, testosterone, epitestosterone, androsterone and etiocolanolone. The questionnaire aims to collect information on background, socioeconomic status, lifestyle factors, parent's pubertal history as well as current height and weight. Quality of life is monitored by KIDSCREEN-52.

Collaborating researchers and departments

Department of Paediatrics, Aalborg University Hospital

• Ann-Margrethe Rønholt Christensen

Department of Paediatrics, Aarhus University Hospital

• Niels Holtum Birkebæk

H.C. Andersen's children's Hospital, Odense University Hospital

• Dorte Hansen

Department of Paediatrics, Zealand University Hospital

• Malene Boas