Clinical trial NCT01411527: The COPENHAGEN Puberty Study
Official title: The COPENHAGEN Puberty Study Providing Normative Data of Healthy Danish Children and Adolescents
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Puberty
Keywords: Hormones
Endocrine Disrupters
Polymorphism, Genetic
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: The Ministry of Science, Technology and Innovation, Denmark
name: European Commission
First posted: 2011-08-08
Enrollment: 1957
Sex: ALL
Minimum age (years): 5
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: In the cross sectional study, all children at randomly selected schools in Copenhagen were invited (6203 children). 1864 accepted to participate.

In the longitudinal study, children at two schools with the highest participating rate were invited to participate in the follow-up study. Ongoing recruitment was continued until at least 100 boys and 100 girls were enrolled in the logitudinal study.

Brief summary: By clinical examinations and withdrawing of blood samples from a large number of healthy Danish children, this study will reveal if age of pubertal onset is declining. Furthermore, the extensive normative data will provide detailed insight into normal ranges and individual changes of anthropometrics and hormone levels in healthy children during childhood and adolescence.

Detailed description: The COPENHAGEN Puberty Study is a combined cross sectional and longitudinal study of healthy Danish children.

All children will be thoroughly examined and blood- and urine samples will be collected at every visit. The families fill out questionaires.

Physical examination: Height; sitting-height; weight; circumference of waist, hip, arm; measurement of fatfolds (biceps, triceps, flank, subscapularis); voice-break (yes/no), blood pressure; pubertal staging according to Tanners classification: breast development (B1-B5), genitalia development boys (G1-G5), pubic hair development (PH1-PH5), axillary hair (yes/no), sweat (yes/no), acne (yes/no

Urine sample: For measurement of FSH, LH and endocrine disrupters.

Blood sample: For measurement of hormone levels (FSH, LH, estradiol, SHBG, testosterone, DHEAS, androstenedione, inhibin A, inhibin B, Insl3, kisspeptin, ghrelin, leptin, IGF-1, IGFBP3, TSH, T4, Free T4, T3, HbA1C, calcium-ion, PTH, phosphate, 25-OH-vitamine D, AMH), endocrine disrupters (PCB´s, dioxines, parabens, phthalates), isolation of DNA and RNA to evaluate relevant polymorphisms.

Questionaire: regarding information of previous growth and health.

Eligibility criteria: Inclusion Criteria:

* all children accepting to participate were included

Exclusion Criteria:

* no children were excluded from examination or blood sampling. In case of chronic diseases, medical treatment, or ethnicity the children may be excluded from specific final data analysis.

Primary outcomes:
measure: Pubertal Onset
timeFrame: up to 8 year period.
Secondary outcomes:
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Growth and Reproduction, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, dept. of Growth and Reproduction
name: Anders Juul, PhD, DMSc
role: STUDY_DIRECTOR
References:
citation: Courant F, Aksglaede L, Antignac JP, Monteau F, Sorensen K, Andersson AM, Skakkebaek NE, Juul A, Bizec BL. Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method. J Clin Endocrinol Metab. 2010 Jan;95(1):82-92. doi: 10.1210/jc.2009-1140. Epub 2009 Nov 20.
citation: Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009 May;123(5):e932-9. doi: 10.1542/peds.2008-2491.
citation: Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010 Jan;95(1):263-70. doi: 10.1210/jc.2009-1478. Epub 2009 Nov 19.
citation: Sorensen K, Aksglaede L, Munch-Andersen T, Aachmann-Andersen NJ, Petersen JH, Hilsted L, Helge JW, Juul A. Sex hormone-binding globulin levels predict insulin sensitivity, disposition index, and cardiovascular risk during puberty. Diabetes Care. 2009 May;32(5):909-14. doi: 10.2337/dc08-1618. Epub 2009 Feb 5.
citation: Juul A, Sorensen K, Aksglaede L, Garn I, Rajpert-De Meyts E, Hullstein I, Hemmersbach P, Ottesen AM. A common deletion in the uridine diphosphate glucuronyltransferase (UGT) 2B17 gene is a strong determinant of androgen excretion in healthy pubertal boys. J Clin Endocrinol Metab. 2009 Mar;94(3):1005-11. doi: 10.1210/jc.2008-1984. Epub 2008 Dec 16.
citation: Sorensen K, Aksglaede L, Munch-Andersen T, Aachmann-Andersen NJ, Leffers H, Helge JW, Hilsted L, Juul A. Impact of the growth hormone receptor exon 3 deletion gene polymorphism on glucose metabolism, lipids, and insulin-like growth factor-I levels during puberty. J Clin Endocrinol Metab. 2009 Aug;94(8):2966-9. doi: 10.1210/jc.2009-0313. Epub 2009 May 5.
citation: Sorensen K, Aksglaede L, Petersen JH, Leffers H, Juul A. The exon 3 deleted growth hormone receptor gene is associated with small birth size and early pubertal onset in healthy boys. J Clin Endocrinol Metab. 2010 Jun;95(6):2819-26. doi: 10.1210/jc.2009-2484. Epub 2010 Apr 9.
citation: Sorensen K, Mouritsen A, Mogensen SS, Aksglaede L, Juul A. Insulin sensitivity and lipid profiles in girls with central precocious puberty before and during gonadal suppression. J Clin Endocrinol Metab. 2010 Aug;95(8):3736-44. doi: 10.1210/jc.2010-0731. Epub 2010 May 19.
citation: Hagen CP, Aksglaede L, Sorensen K, Main KM, Boas M, Cleemann L, Holm K, Gravholt CH, Andersson AM, Pedersen AT, Petersen JH, Linneberg A, Kjaergaard S, Juul A. Serum levels of anti-Mullerian hormone as a marker of ovarian function in 926 healthy females from birth to adulthood and in 172 Turner syndrome patients. J Clin Endocrinol Metab. 2010 Nov;95(11):5003-10. doi: 10.1210/jc.2010-0930. Epub 2010 Aug 18.
citation: Aksglaede L, Sorensen K, Boas M, Mouritsen A, Hagen CP, Jensen RB, Petersen JH, Linneberg A, Andersson AM, Main KM, Skakkebaek NE, Juul A. Changes in anti-Mullerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab. 2010 Dec;95(12):5357-64. doi: 10.1210/jc.2010-1207. Epub 2010 Sep 15.
citation: Mogensen SS, Aksglaede L, Mouritsen A, Sorensen K, Main KM, Gideon P, Juul A. Diagnostic work-up of 449 consecutive girls who were referred to be evaluated for precocious puberty. J Clin Endocrinol Metab. 2011 May;96(5):1393-401. doi: 10.1210/jc.2010-2745. Epub 2011 Feb 23.
citation: Aksglaede L, Christiansen P, Sorensen K, Boas M, Linneberg A, Main KM, Andersson AM, Skakkebaek NE, Juul A. Serum concentrations of Anti-Mullerian Hormone (AMH) in 95 patients with Klinefelter syndrome with or without cryptorchidism. Acta Paediatr. 2011 Jun;100(6):839-45. doi: 10.1111/j.1651-2227.2011.02148.x. Epub 2011 Feb 25.
citation: Frederiksen H, Aksglaede L, Sorensen K, Nielsen O, Main KM, Skakkebaek NE, Juul A, Andersson AM. Bisphenol A and other phenols in urine from Danish children and adolescents analyzed by isotope diluted TurboFlow-LC-MS/MS. Int J Hyg Environ Health. 2013 Nov;216(6):710-20. doi: 10.1016/j.ijheh.2013.01.007. Epub 2013 Mar 13.
citation: Mouritsen A, Hagen CP, Sorensen K, Aksglaede L, Mieritz MG, Main KM, Almstrup K, Rajpert-De Meyts E, Juul A. Androgen receptor CAG repeat length is associated with body fat and serum SHBG in boys: a prospective cohort study. J Clin Endocrinol Metab. 2013 Mar;98(3):E605-9. doi: 10.1210/jc.2012-3778. Epub 2013 Feb 7.
citation: Mouritsen A, Aksglaede L, Soerensen K, Hagen CP, Petersen JH, Main KM, Juul A. The pubertal transition in 179 healthy Danish children: associations between pubarche, adrenarche, gonadarche, and body composition. Eur J Endocrinol. 2012 Dec 31;168(2):129-36. doi: 10.1530/EJE-12-0191. Print 2013 Feb.
citation: Hilsted L, Rustad P, Aksglaede L, Sorensen K, Juul A. Recommended Nordic paediatric reference intervals for 21 common biochemical properties. Scand J Clin Lab Invest. 2013 Feb;73(1):1-9. doi: 10.3109/00365513.2012.721519. Epub 2012 Sep 26.
citation: Mieritz MG, Frederiksen H, Sorensen K, Aksglaede L, Mouritsen A, Hagen CP, Skakkebaek NE, Andersson AM, Juul A. Urinary phthalate excretion in 555 healthy Danish boys with and without pubertal gynaecomastia. Int J Androl. 2012 Jun;35(3):227-35. doi: 10.1111/j.1365-2605.2012.01279.x.
citation: Frederiksen H, Sorensen K, Mouritsen A, Aksglaede L, Hagen CP, Petersen JH, Skakkebaek NE, Andersson AM, Juul A. High urinary phthalate concentration associated with delayed pubarche in girls. Int J Androl. 2012 Jun;35(3):216-26. doi: 10.1111/j.1365-2605.2012.01260.x. Epub 2012 Mar 19.
citation: Hagen CP, Aksglaede L, Sorensen K, Mouritsen A, Andersson AM, Petersen JH, Main KM, Juul A. Individual serum levels of anti-Mullerian hormone in healthy girls persist through childhood and adolescence: a longitudinal cohort study. Hum Reprod. 2012 Mar;27(3):861-6. doi: 10.1093/humrep/der435. Epub 2012 Jan 2.
citation: Busch AS, Hagen CP, Main KM, Pereira A, Corvalan C, Almstrup K, Mericq V, Juul A. Genetic Variation of Follicle-Stimulating Hormone Action Is Associated With Age at Testicular Growth in Boys. J Clin Endocrinol Metab. 2017 May 1;102(5):1740-1749. doi: 10.1210/jc.2016-4013.
citation: Busch AS, Hagen CP, Almstrup K, Juul A. Circulating MKRN3 Levels Decline During Puberty in Healthy Boys. J Clin Endocrinol Metab. 2016 Jun;101(6):2588-93. doi: 10.1210/jc.2016-1488. Epub 2016 Apr 8.
citation: Almstrup K, Lindhardt Johansen M, Busch AS, Hagen CP, Nielsen JE, Petersen JH, Juul A. Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. Sci Rep. 2016 Jun 28;6:28657. doi: 10.1038/srep28657.
citation: Busch AS, Ljubicic ML, Upners EN, Fischer MB, Kolby N, Eckert-Lind C, Jespersen K, Andersson AM, Frederiksen H, Johannsen TH, Hegaard HK, Sharif H, Hagen CP, Juul A. Cohort profile: The COPENHAGEN Minipuberty Study-A longitudinal prospective cohort of healthy full-term infants and their parents. Paediatr Perinat Epidemiol. 2021 Sep;35(5):601-611. doi: 10.1111/ppe.12777. Epub 2021 Jun 22.
citation: Albrethsen J, Ljubicic ML, Juul A. Longitudinal Increases in Serum Insulin-like Factor 3 and Testosterone Determined by LC-MS/MS in Pubertal Danish Boys. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa496. doi: 10.1210/clinem/dgaa496.
citation: Busch AS, Hojgaard B, Hagen CP, Teilmann G. Obesity Is Associated with Earlier Pubertal Onset in Boys. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz222. doi: 10.1210/clinem/dgz222.
citation: Busch AS, Hollis B, Day FR, Sorensen K, Aksglaede L, Perry JRB, Ong KK, Juul A, Hagen CP. Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI. Hum Reprod. 2019 Aug 1;34(8):1514-1522. doi: 10.1093/humrep/dez118.
citation: Busch AS, Hagen CP, Assens M, Main KM, Almstrup K, Juul A. Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls. J Clin Endocrinol Metab. 2018 Jan 1;103(1):228-234. doi: 10.1210/jc.2017-01860.
citation: Kolby N, Busch AS, Aksglaede L, Sorensen K, Petersen JH, Andersson AM, Juul A. Nocturnal Urinary Excretion of FSH and LH in Children and Adolescents With Normal and Early Puberty. J Clin Endocrinol Metab. 2017 Oct 1;102(10):3830-3838. doi: 10.1210/jc.2017-01192.
citation: Lindhardt Johansen M, Hagen CP, Mieritz MG, Wolthers OD, Heuck C, Petersen JH, Juul A. Pubertal Progression and Reproductive Hormones in Healthy Girls With Transient Thelarche. J Clin Endocrinol Metab. 2017 Mar 1;102(3):1001-1008. doi: 10.1210/jc.2016-2871.
citation: Bisgaard A, Sorensen K, Johannsen TH, Helge JW, Andersson AM, Juul A. Significant gender difference in serum levels of fibroblast growth factor 21 in Danish children and adolescents. Int J Pediatr Endocrinol. 2014;2014(1):7. doi: 10.1186/1687-9856-2014-7. Epub 2014 May 23.
citation: Nielsen J, Jensen RB, Juul A. Increased sex hormone-binding globulin levels in children and adolescents with thyrotoxicosis. Horm Res Paediatr. 2013;79:157-61. doi: 10.1159/000348837. Epub 2013 Mar 27.
citation: Hagen CP, Sorensen K, Anderson RA, Juul A. Serum levels of antimullerian hormone in early maturing girls before, during, and after suppression with GnRH agonist. Fertil Steril. 2012 Nov;98(5):1326-30. doi: 10.1016/j.fertnstert.2012.07.1118. Epub 2012 Aug 14.