Copenhagen Mini Puberty Study - EDMARC

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The Copenhagen Mini-puberty Study
Recruitment started September 2016 and was completed ultimo 2019
What is Mini-puberty?
Sexual maturation is a process that results in reproductive capability and starts with the activation of the hypothalamic-pituitary-gonadal hormone axis (HPG-axis). In many animals this activation happens shortly after birth. However, in primates, including humans, the early activation of the HPG-axis is only transient (the so-called mini-puberty) and starting from 3-6 months of age it is turned off again in humans. Human sexual maturation is thus not continued until the HPG-axis is reactivated at puberty onset. The mechanisms behind the inhibition of the human HPG axis in infancy remain unknown.

Research on human sexual maturation has mainly focused on the period immediately prior to, during, and after the onset of puberty in order to understand why some children mature early, some late and why some reproductive diseases occur. However, to understand how sexual maturation is regulated in humans it may in fact be relevant to elucidate the regulation of mini-puberty including the factors involved in shutting down the HPG-axis in infancy until it is reactivated again in puberty.

Aims and Study Design
The COPENHAGEN Mini-puberty Study was launced with the aim to study mini-puberty in healthy newborns compared to in newborns born with symptoms of differences in sex development (DSD). The aims was to:
- describe the dynamic changes of the HPG-axis during minipuberty
- identify factors that explain inhibition of the HPG-axis following mini-puberty
- improve our understanding of the regulation of normal puberty and sexual maturation
- gaining insight into causes of DSD.
It is a unique, prospective study of 200 healthy newborns and their parents, recruited during pregnancy and newborns with DSD recruited on referral to our clinic. All babies are examined clinically including anthropometric measurements, and blood samples (analysed for reproductive hormones, genetic polymorphisms, DNA methylation) and urine samples were collected with 2 month intervals between birth and one year of age. For study design details see below or Busch et al. 2021.

The study was approved by (# NCT02784184) and the local ethics committee (H15014876).
Data analysis and use of samples from the generated biobank is on-going.

Publications and Dissertations from the study per. April 2023 are listed below.

Principal and Senior Investigators
Anders Juul, professor, M.D., D.MSc, PhD (PI)
Casper Hagen, M.D., D.MSc, PhD
Rikke Beck, M.D., PhD
Several young researchers and Ph.D-students have been involved in the study

Main Sponsors
Aase og Ejnar Danielsens Fond
Region Hovedstadens Forskningspulje

Lærkeholm Müller M, Busch AS, Ljubicic ML, Upners EN, Fischer MB, Hagen CP, Albrethsen J, Frederiksen H, Juul A, Andersson AM. Urinary concentration of phthalates and bisphenol A during minipuberty is associated with reproductive hormone concentrations in infant boys. Int J Hyg Environ Health, 2023 May;250:114166. doi: 10.1016/j.ijheh.2023.114166.

Ljubicic ML, Johannsen TH, Fischer MB, Upners EN, Busch AS, Main KM, Andersson AM, Hagen CP, Juul A. Serum LH/FSH ratios in 87 infants with differences of sex development. Endocr Connect. 2023 Feb 23;12(3):e220275. doi: 10.1530/EC-22-0275.

Ljubicic ML, Madsen A, Upners EN, Fischer MB, Busch AS, Frederiksen H, Johannsen TH, Juul A, Hagen CP. Longitudinal evaluation of breast tissue in healthy infants: Prevalence and relation to reproductive hormones and growth factors. Front Endocrinol (Lausanne). 2022 Dec 1;13:1048660. doi: 10.3389/fendo.2022.1048660.

Frederiksen H, Ljubicic ML, Upners EN, Fischer MB, Busch AS, Hagen CP, Juul A, Andersson AM. Benzophenones, bisphenols and other polychlorinated/phenolic substances in Danish infants and their parents - including longitudinal assessments before and after introduction to mixed diet. Environ Int. 2022
Nov;169:107532. doi: 10.1016/j.envint.2022.107532.

Ljubicic ML, Busch AS, Upners EN, Fischer MB, Petersen JH, Raket LL, Frederiksen H, Johannsen TH, Juul A, Hagen CP. A Biphasic Pattern of Reproductive Hormones in Healthy Female Infants: The COPENHAGEN Minipuberty Study. J Clin Endocrinol Metab. 2022 Aug 18;107(9):2598-2605. doi: 10.1210/clinem/dgac363.

Ljubicic ML, Busch AS, Upners EN, Fischer MB, Main KM, Andersson AM, Johannsen TH, Hagen CP, Juul A. Dynamic changes in LH/FSH ratios in infants with normal sex development. Eur J Endocrinol. 2022 Jun 1;187(1):135-142. doi: 10.1530/EJE-21-0999.

Busch AS, Ljubicic ML, Upners EN, Fischer MB, Raket LL, Frederiksen H, Albrethsen J, Johannsen TH, Hagen CP, Juul A. Dynamic Changes of Reproductive Hormones in Male Minipuberty: Temporal Dissociation of Leydig and Sertoli Cell Activity. J Clin Endocrinol Metab. 2022 May 17;107(6):1560-1568. doi: 10.1210/clinem/dgac115.

Frederiksen H, Upners EN, Ljubicic ML, Fischer MB, Busch AS, Hagen CP, Juul A, Andersson AM. Exposure to 15 phthalates and two substitutes (DEHTP and DINCH) assessed in trios of infants and their parents as well as longitudinally in infants exclusively breastfed and after the introduction of a mixed diet. Environ Int. 2022 Mar;161:107107. doi: 10.1016/j.envint.2022.107107.

Upners EN, Ljubicic ML, Busch AS, Fischer MB, Almstrup K, Petersen JH, Jensen RB, Hagen CP, Juul A. Dynamic Changes in Serum IGF-I and Growth During Infancy: Associations to Body Fat, Target Height, and PAPPA2 Genotype. J Clin Endocrinol Metab. 2022 Jan 1;107(1):219-229. doi: 10.1210/clinem/dgab653.

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.

Fischer MB, Ljubicic ML, Hagen CP, Thankamony A, Ong K, Hughes I, Jensen TK, Main KM, Petersen JH, Busch AS, Upners EN, Sathyanarayana S, Swan SH, Juul A.
Anogenital Distance in Healthy Infants: Method-, Age- and Sex-related Reference Ranges. J Clin Endocrinol Metab. 2020 Sep 1;105(9):2996–3004. doi: 10.1210/clinem/dgaa393.
Dept. of Growth and Reproduction
Copenhagen University Hospital, Rigshospitalet
Blegdamsvej 9
DK-2100 Copenhagen Denmark

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