BACKGROUND: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation.
OBJECTIVE: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring.
METHODS: Healthy, singleton pregnant women and their partners.
METHODS: The COPANA cohort is a prospective, observational pregnancy and birth cohort.
METHODS: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus.
RESULTS: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022).
CONCLUSIONS: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring.

Serum Anti-Mullerian Hormone (AMH) concentrations have been proposed as a marker of spontaneous puberty and future fertility in Turner syndrome (TS). Gonadotropins during minipuberty may also provide a clue to ovarian function but there is insufficient data to inform utility in the routine clinical management of TS. Our objective was to describe the distribution of AMH in a cross-sectional cohort of patients in a TS specialty clinic, and correlate with spontaneous puberty and karyotype, as well as gonadotropins during the minipuberty of infancy in a smaller subset of patients aged 2-9 months.
Retrospective chart review of patients seen in the TS clinic at Children\'s National Hospital from 1/1/2019 to 8/24/2022, to assess AMH and correlate with karyotype and spontaneous puberty.
Among 114 patients (median age 9.6 year, 0.08-22 year), AMH values were detectable in only (40/104) 38%, and higher mean AMH (2.7 ± 0.95 ng/mL) was seen in mosaic 45,X/46,XX karyotype compared to 45,X (0.03 ± 0.14 ng/mL) (p < .001), and structurally abnormal-X karyotype (0.11 ± 0.5) (p = .0003). Mean AMH was higher (1.4 ± 1.6 ng/mL) among those with spontaneous menarche compared with spontaneous thelarche but no menarche. AMH was detectable in 2/10 during minipuberty in those with the lowest luteinizing hormone (LH).
Our institutional data reflects a diverse cohort of patients seen in a TS specialty clinic in the United States, showing correlation of AMH with karyotype and spontaneous menarche, as well as description of gonadotropins during minipuberty highlighting their clinical relevance. Studies in larger, prospective longitudinal cohorts will help determine their predictive value and role in the care of TS.

UNASSIGNED: The aim of our single-center case-control study is to evaluate whether minipuberty occurs in patients with hypoxic ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). We intend to conduct this evaluation by confronting the values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the values of testosterone in males and estradiol in females between newborns with HIE and in subsequent TH and healthy controls.
UNASSIGNED: We enrolled 40 patients (age: 56-179 days; 23 males), of whom 20 met the inclusion criteria for the case group and who underwent TH. A blood sample was taken from each patient at approximately 10 weeks of age to evaluate FSH and LH from the serum samples of all patients and to evaluate 17-beta estradiol (E2) and testosterone levels, respectively, from the serum samples of female and male patients.
UNASSIGNED: It was found that minipuberty occurred in the case group patients, with no significant differences reported from the control group and with hormonal serum levels comparable to healthy infants of the control group (FSH 4.14 mUI/ml ± 5.81 SD vs. 3.45 mUI/ml ± 3.48 SD; LH 1.41 mUI/ml ±1.29 SD vs. 2.04 mUI/ml ±1.76 SD; testosterone in males 0.79 ng/ml ± 0.43 SD vs. 0.56 ng/ml ± 0.43 SD; 17-beta estradiol in females 28.90 pg/ml ± 16.71 SD vs. 23.66 pg/ml ± 21.29 SD).
UNASSIGNED: The results of the present study may pave the way for further research and the evaluation of more possible advantages of TH.

Minipuberty, a period of a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in both sexes, enables evaluation of gonadal function in infants suspected of hypogonadism. However, female minipuberty remains poorly elucidated.
We aimed to establish continuous reference ranges for the most commonly used reproductive hormones and to evaluate the dynamics of the HPG axis in females aged 0 to 1 year.
The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), a longitudinal, prospective cohort study.
Healthy infants from Copenhagen.
A total of 98 healthy, term female infants followed with 6 examinations including venipuncture during the first year of life.
None.
Serum concentrations of LH, FSH, inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and SHBG were quantified using highly sensitive methods in 266 serum samples.
Reference ranges were established for LH, FSH, inhibin B, AMH, E1, E2, and SHBG. Two peaks were observed in normalized mean curves for all hormones. The first peaks were timed around postnatal days 15 to 27 followed by a general nadir for all hormones around days 58 to 92. The second peaks occurred around days 107 to 125 for inhibin B, AMH, E1, E2, and SHBG and days 164 to 165 for LH and FSH.
We present age-related, continuous reference ranges of the most commonly used reproductive hormones and present novel data revealing a biphasic and prolonged female minipuberty.
NCT02784184.

To evaluate minipuberty (MP) in small for gestational age (SGA) infants, both preterm and full-term, during the first year of life.
33 SGA healthy newborns (group A), 21 of which full-term (subgroup A1) and 12 preterm (A2) were enrolled. Control group (B) consisted of 27 AGA, 17 full-term (subgroup B1) and 10 preterm (B2) infants. Growth parameters, FSH, LH, and Estradiol (E2) or Testosterone (T) serum levels were monitored at 3, 6, and 12 months.
The gonadotropin surge reached greater increase of LH in males at 3 months and FSH in females at 3, 6 and 12 months (p < 0.001). In male infants: T at 3 months was higher in subgroup A2 vs A1(p = 0.001), and correlated negatively with gestational age (GA, p < 0.005), length and weight at birth (p < 0.05); LH was higher in subgroup B2 vs B1 at 6 months (p = 0.003), and in group A vs B at 12 months (p = 0.03). Females displayed higher E2 at 6 months in B2 vs B1 (p < 0.05), negatively correlated with GA and weight gain (p < 0.05); LH at 6 months was increased in A2 vs A1 (p = 0.03). Overall, preterm males displayed higher T at 3 months (p = 0.001), LH at 3, 6 and 12 months (p < 0.05), and LH/FSH ratio at 6 months (p = 0.001). Preterm females exhibited increased LH/FSH ratio at 3 and 6 months (p < 0.05).
Irrespectively of GA, MP occurred with a typical sexual dimorphism and exhibited sex-specific correlations between hormones and perinatal parameters. SGA condition and prematurity seemed to enhance and protract MP over time in both sexes.

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.
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.
Healthy, Danish, full-term, singleton newborns including their parents.
Single-centre, prospective, observational longitudinal pregnancy and birth cohort.
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.
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).
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.