Cohort profile: The COPENHAGEN Minipuberty Study—A longitudinal prospective cohort of healthy full‐term infants and their parents

Abstract

Background The hypothalamic‐pituitary‐gonadal (HPG) axis governs sexual maturation and reproductive function in humans. In early postnatal life, it is transiently active during which circulating sex steroids reach adult levels. While this so‐called minipuberty represents a universal phenomenon in infants of both sexes, its role for early maturation and growth remains incompletely understood. Objectives To provide normative data on auxology as well as serum and urinary hormone levels in healthy, full‐term infants throughout the first year of life and to investigate associations of postnatal HPG axis dynamics as well as hormonal, genetic and environmental exposures with early genital development and growth. Population Healthy, Danish, full‐term, singleton newborns including their parents. Design Single‐centre, prospective, observational longitudinal pregnancy and birth cohort. Methods Newborns were followed with six repeated clinical examinations during a one‐year follow‐up period. An umbilical cord blood sample was drawn at birth. At each visit, infants underwent a clinical examination focusing on auxology and genital development. Further, blood (serum, plasma, DNA) and urine samples were collected at each visit. Mothers and fathers underwent a clinical examination and provided blood samples prior to and after birth. A subset of parents provided urine samples and breast milk samples. Pregnancy and obstetrical outcomes, and detailed parental questionnaires were compiled. Preliminary results Between August 2016 and August 2018, 2481 women with singleton pregnancies were invited to participate of which 298, including their partners, were enrolled (12.0%). A total of 268 healthy, full‐term newborns born appropriate for gestational age (AGA) were included at birth, 233 newborns participated in the postnatal follow‐up period and 186 completed the one‐year follow‐up period (9.4% and 7.5%, respectively). Conclusion The COPENHAGEN Minipuberty Study provides detailed, longitudinal data on early genital development and growth including hormonal and genetic profiles and environmental exposure in healthy infants including additional data in their parents.

Clinical aspects of histological and hormonal parameters in boys with cryptorchidism

“…Despite the presence of high testosterone and FSH, spermatogenesis does not progress since immature Sertoli cells are devoid of androgen receptors. Minipuberty may also have an important impact on secondary sex characteristics and other biological functions [65,73].…”

Longitudinal evaluation of breast tissue in healthy infants: Prevalence and relation to reproductive hormones and growth factors

“…Aside from the novel use of PCA, the strengths of this study included: 1) the design of the cohort of healthy infants followed longitudinally allowing for the description of both prevalence and the progression of breast tissue in infancy; 2) the rather large study size of 233 infants; 3) the frequent serum sampling; and 4) the use of highly sensitive hormone analytical methods. However, the study also had limitations which included: 1) due to limitations in serum sample volumes, estrogens were not quantified in boys and androgens were not quantified in girls; 2) all infants were Caucasian which restricts generalizability; 3) the measurement of the size of the breast tissue can be difficult and interobserver variation has previously been noted in both the current cohort ( 30 ) as well as other cohorts ( 5 ). This interobserver variation, which may also have been affected by infant weight/body size, could possibly have been limited by the use of breast ultrasound, which reportedly has a small intra- and interobserver variation ( 46 ); 4) infants contributed with multiple observations in the Spearman’s rho analyses, yet the distribution of the multiple samples was random and there was no reason to believe that those who included more observations were outliers/at ends of the given scales; 5) the cohort was recruited in affluent areas of Copenhagen and consequently very few infants were formula-fed vs. breast milk-fed, which may have hidden true differences between the groups; and 6) post-hoc correction for multiple testing was not performed as it would have obscured the significant associations presented in the study.…”

“…A total of 186 infants completed the entire follow-up period. Further details on the design of the study have previously been described ( 30 ). All included infants were healthy and, importantly, not suspected of any endocrinological disorders.…”

“…Due to limitations of the amount of blood that can be drawn from a healthy infant for research purposes (ethically as well as physically, refer to Busch et al. ( 30 ) for details), there was not a complete overlap in the hormones analyzed between the two sexes. In girls, LH, follicle-stimulating hormone (FSH), inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), sex hormone-binding globulin (SHBG), IGF-I, and insulin-like growth factor-binding protein 3 (IGFBP3) were quantified.…”

Serum LH/FSH ratios in 87 infants with differences of sex development

“…Statistical analyses were carried out using IBM Statistics SPSS, version 22. Data from the included patients in this study were plotted against age-related LH/FSH ratio cutoffs previously published by our group based on healthy infants from The COPENHAGEN Minipuberty Study (3,18). For details pertaining to the receiver-operating analysis-derived cutoffs, please refer to (3).…”