COPENHAGEN Minipuberty Study

Child Development Clinical Trial

— CPHMINIPUB  

Official title:

COPENHAGEN Minipuberty Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02784184
• Other study ID #: RH-H-15014876
• Secondary ID: RH-2015-210-0414
• Status: Active, not recruiting
• Start date: August 2016
• Est. completion date: December 31, 2019

Study information

• Verified date: February 2019
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Minipuberty is a term used to describe the transient activation of the pituitary-gonadal axis 2-3 months after birth in both boys and girls. It is, however, not known why infants reach adult levels of reproductive hormones in early life, nor is the exact timing of the peak known. Furthermore, what determines the timing of peaks and suppressions of reproductive hormones from infancy throughout childhood and into adolescence remains to be elucidated.

The study aims to described and evaluate dynamic changes in the hypothalamic-pituitary- gonadal axis in early postnatal life.

Description:

Minipuberty is a term used to describe the transient activation of the pituitary-gonadal axis 2-3 months after birth in both boys and girls. It is, however, not known why infants reach adult levels of reproductive hormones in early life, nor is the exact timing of the peak known. Furthermore, what determines the timing of peaks and suppressions of reproductive hormones from infancy throughout childhood and into adolescence remains to be elucidated.

Few studies have investigated minipuberty and one, for example, found that it is affected in premature infants (before gestation week 37). However, no studies on normative data throughout minipuberty in infants exist.

Furthermore, using minipuberty as a window for diagnosis of endocrine disorders and future reproductive function has been suggested. Defining minipuberty, both in terms of circulating hormone levels and urinary metabolites, in healthy infants is therefore essential in order to utilize this window. Studies using patients with Disorders of Sex Development during minipuberty have been carried out, but they are hampered by small sample sizes and lack of control groups.

In addition, little is known about the genetic and epigenetic factors that drive the onset, progression and termination of minipuberty as well as the actual puberty, i.e. the factors responsible for the quiescence of the HPG axis during childhood and the dis-inhibition responsible for pubertal onset. Therefore, much attention was drawn on the study performing whole exome sequencing in patients and relatives with central precocious puberty (CPP). For the first time, MKRN3 was suggested as the primary factor responsible for HPG inhibition during mid-childhood. A number of studies support that MKRN3 mutations cause CPP, and genetic variation of MKRN3 affect pubertal timing in healthy girls. Our findings of declining serum levels of MKRN3 prior to pubertal onset in healthy girls support MKRN3 as a regulator of pubertal onset. The exact mechanism through which MRKN3 exceeds its effect remains to be elucidated; however, its zink-finger structure indicates regulation of superior cellular processes such as epigenetic regulation of DNA transcription.

Twin studies suggest that 60% of the inter-individual variation is caused by genetic factors. However, genome wide association (GWA) studies only explain a fraction of the variation in age at puberty. Recently, our research group has revealed the largest effect of a single SNP on age at pubertal onset in girls. The location of the SNPs in genes regulating FSH action emphasizes the need of a wide focus including downstream processes in the HPG axis when evaluating factors regulating puberty.

In general, the abovementioned studies have led to a spark in the interest in epigenetic studies, i.e. studies of genetic changes that are not caused by changes in the DNA sequences themselves, but rather regulatory mechanisms of DNA expression. Generally, this is thought to include DNA methylation, histone modifications and small RNAs. Epi-mutations (improper epigenetic regulation) possibly account for more of the variation in puberty than genetic factors. Previously, both gene-specific and genome-wide DNA methylation patterns have been studied. Genome-wide hypomethylation seen in peripheral leukocytes has been shown to be linked with an array of cancers, including colorectal cancers. As multiple histone modifications exist and analysis requires special sample treatment procedures, DNA methylation is the most appropriate epigenetic marker to analyze. A study of rats found that specific gene hypomethylation was accountable for lack of pubertal onset, but the link between epigenetics and mini- and pubertal timing and progression has, however, only scarcely been studied. Understanding this link would greatly add to our knowledge of reproductive function and normal sex development.

Disorders of Sex Development (DSD) is an umbrella term covering conditions with congenital disordered development of chromosomal, gonadal or anatomical sex. Genital abnormalities may include as many as up to 4-6 in 1000 births, although individual disorders are much rarer, e.g. 45,X/46,XY mosaicism is seen in about 1 in 15000 live births. Previously DSD diagnoses were labeled with different and often imprecise terms such as 'intersex', 'sex reversal' and 'hermaphroditism' etc. In 2006, DSD nomenclature was renamed and grouped according to genetic sex into sex chromosome DSD, 46,XY DSD and 46,XX DSD.

DSD patients are diagnosed at different periods in life depending on their diagnosis, phenotype and primary and secondary sexual development. Patients with sex chromosome DSD can be diagnosed at prenatal screenings, patients with affected external genitalia at birth, some during childhood due to growth abnormalities, some during adolescence due to abnormal pubertal progression and lastly, some in adulthood due to infertility.

Understanding normal sex development is therefore the key to identifying and optimizing diagnosis and treatment of patients with DSD. A project, as the present, that seeks to investigate normal minipuberty while comparing to minipuberty in patients with DSD is therefore of great importance. Furthermore, knowledge of the genetic and epigenetic control mechanisms of minipuberty will aid the understanding of reproductive physiology and in particular DSD pathology.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 280
• Est. completion date: December 31, 2019
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 12 Months

Eligibility

Inclusion Criteria:

• Singleton pregnancy

• Maternal and paternal Caucasian origin

• Maternal pre-pregnancy BMI between 18 and 35 kg/m2

• No serious maternal illness, including no pre-existing maternal diabetes nor thyroid gland diseases

• Term pregnancy (week 37+0 to 41+7)

• No gestational diabetes

• No fetal malformations or chromosomal disorders

• Birth weight of child between 3rd and 97th percentile

Only healthy infants born at term will be included in the study which all prospective participants will be informed of.

Exclusion Criteria:

Related Conditions & MeSH terms

• Child Development
• Disorders of Sex Development

Locations

Country	Name	City	State
Denmark	Department of Growth and Reproduction, Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum and urinary metabolites of reproductive hormones (e.g. steroid hormone metabolites and gonadotropins) (newborn)	change/course serum and urinary metabolites	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth plus 40 days daily measurement (urine, female 40 days diaper study subgroup)
Primary	Urinary metabolites of endocrine disrupting chemicals (e.g. phthalates, phenols, perfluorinated compounds and parabens) (newborn)	change/course urinary metabolites	3-7d, & 1,3,5,7,12m or 2,4,6,8,12m after birth plus 40 days daily measurement (urine, female 40 days diaper study subgroup)
Primary	Basic clinical examination (newborn) (size and proportions)	change/course: measurements of length, weight, skin folds and hip-waist ratio	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Basic clinical examination (newborn) (pubertal staging)	change/course: pubertal staging using Tanners classification (including testicular size in boys assessed by Prader's orchidometer and ultrasound	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Basic clinical examination (newborn) (genitalia)	change/course: classification of external genitalia (classification of genital tubercle, location of gonads, position of urethra, labia/scrotal fusion)	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Basic clinical examination (newborn) (penile measurement)	change/course: penile measurement with a ruler (in boys)	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Basic clinical examination (newborn) (AGD)	change/course: ano-genital distance (AGD) measured with a ruler	3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Genetic profiling	Genotyping of different genetic loci (genetic variation of loci regulating hormone signalling, e.g. FSHB, etc.)	single determination or 3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Primary	Epigenetic profiling	change/course: epigenetic variation of loci regulating hormone signalling	single determination or 3-7d, and 1,3,5,7,12m or 2,4,6,8,12m after birth
Secondary	Basic clinical examination (parents) (height)	Height	postpartal (within first 3 months)
Secondary	Basic clinical examination (parents) (weight)	self-reported pre-pregnancy weight for the mother and postpartal weight of the father	postpartal (within first 3 months)
Secondary	Basic clinical examination (parents)	Skinfolds measured above the biceps, triceps, at the flank, and below the scapula	postpartal (within first 3 months)
Secondary	Pregnancy and perinatal outcome (newborn and mother)	Perinatal outcome including birth weight, -length, partus mode, adverse events/complications, pre- and perinatal drug intake, pregnancy outcomes including gestational age, pregnancy complications, IVF Treatment etc.	before birth and perinatal phase
Secondary	Medical history and exposure (parents) (basic)	Basic medical history (parents) (questionaire / journal)	postpartal (within first year)
Secondary	Medical history and exposure (parents) (obstetrical)	Obstetrical history including outcomes of previous pregnancies and births (mother), smoking and drug intake during pregnancy (mother) (questionaire / journal)	postpartal (within first year)
Secondary	Medical history and exposure (parents) (puberty)	Pubertal history (parents) including age at menarche, pubertal timing with regard to peers, age at menopause of the mother of the parents etc. (questionaire)	postpartal (within first year)
Secondary	Breastfeeding and food intake (newborn)	change/course: breastfeeding and food intake of the newborn during the course of the first year (questionaire)	first year of life