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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. Objectives: 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. Population: Healthy, singleton pregnant women and their partners. Design: 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. Preliminary 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. [ABSTRACT FROM AUTHOR]

Context Nonprogressive premature thelarche (PT) is a self-limiting variant of early puberty, while idiopathic central precocious puberty (ICPP) is a disorder that causes progressive development of secondary sexual characteristics and often requires treatment. The diagnostic differentiation between these conditions is important but can be challenging since they often both initially present clinically with isolated breast development. Objective To describe relevant clinical variables in a large cohort of girls referred for early puberty, and to evaluate clinical and biochemical parameters to distinguish between girls with ICPP and PT. Methods This retrospective study included 1361 girls referred with signs of early puberty to a single, tertiary center from 2009 to 2019. We evaluated clinical presentation, medical history, growth velocity, bone age, hormonal serum concentrations, and gonadotropin-releasing hormone (GnRH) test results. Results Central precocious puberty was diagnosed in 11% (ICPP: n = 143, organic CPP: n = 11) girls, whereas 8% (n = 91 girls) presented with PT. Receiver operating characteristic (ROC) analysis showed several biochemical and anthropometric markers as potential parameters to differentiate between ICPP and PT; however, none were individually adequate. Principal component analysis (PCA)–derived clinical and hormone profiles could predict girls with ICPP from girls with PT with a specificity of 90% and sensitivity of 84%, outperforming any single marker. Conclusion Differentiation of girls with ICPP and PT can be supported by individual clinical and biochemical parameters. However, dimension reduction of clinical and hormonal profiles by PCA improved the diagnostic value, which in the future may support the diagnostic process as a supplement to the GnRH test in evaluation of pubertal disorders. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may affect the male reproductive system as it uses angiotensin‐converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long‐term effects of mild coronavirus disease 2019 (COVID‐19) on testicular function, and insulin‐like factor 3 (INSL3) levels have not previously been assessed during acute SARS‐CoV‐2 infection. Objectives: The aim of the study was to assess the impact of acute SARS‐CoV‐2 infection on testicular function including INSL3 and the presence of SARS‐CoV‐2 RNA in semen in non‐hospitalised men with mild COVID‐19. Materials and methods: This longitudinal study included 36 non‐hospitalised SARS‐CoV‐2‐positive men (median age 29 years). Inclusion was within seven days following a positive SARS‐CoV‐2 reverse‐transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS‐CoV‐2 RNA in oropharyngeal and semen samples were assessed during acute SARS‐CoV‐2 infection (baseline) and at three‐ and six‐month follow‐up. Wilcoxon matched‐pair signed‐rank (two samples) test was used to assess time‐related alterations in reproductive hormone levels and semen parameters. Results: Lower plasma testosterone (T) (total and calculated free (c‐fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS‐CoV‐2 infection (baseline) compared to three‐ and six‐month follow‐up. Consequently, ratios of c‐fT/LH were lower at baseline compared to three‐ and six‐month follow‐up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three‐month follow‐up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six‐month follow‐up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS‐CoV‐2‐related fever episodes or not. No SARS‐CoV‐2 RNA was detected in semen at any time point. Discussion and conclusion: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS‐CoV‐2 infection. The risk of transmission of SARS‐CoV‐2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS‐CoV‐2 cannot be excluded. [ABSTRACT FROM AUTHOR]

Context: Supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations have been a matter of concern in children treated with GH because high IGF-I levels were associated with risk of later disease in former epidemiological studies. Objective: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. Methods: We included 6459 healthy participants (cross-sectional=5326; longitudinal=1133) aged 0-76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment. Intraindividual tracking of IGF-I and IGFBP-3 (SD score [SDS]) was determined by intraclass correlation coefficients (ICCs). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS trajectory from 0 to 76 years. Results: For IGF-I (SDS), ICCs were 0.50 (95% CI, 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12 723±3691 SD) than in male participants (12 563±3393); P=0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9512±1889 to 11 271±1689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD±0.57 to -0.35 SD±0.49. Conclusion: Because IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population. [ABSTRACT FROM AUTHOR]

Introduction: Breast tissue in infancy is a rather undescribed phenomenon. We aimed to describe the prevalence and progression of palpable breast tissue in healthy boys and girls aged 0-1 years and to evaluate clinical markers, individual serum hormone concentrations as well as combined hormone profiles as determinants of the persistence of breast tissue. Methods: In total, 233 term infants (119 boys, 114 girls) were included and followed from birth until 1 year of age in The COPENHAGEN Minipuberty Study (ClinicalTrials.gov #NTC02784184). Infants were followed up to six times with a clinical examination and serum sampling. Principal component analyses (PCAs) produced combined hormone profiles. Results: A total of 98% of all infants aged 0-1 year exhibited breast tissue at some point. 50% still had breast tissue present at 0.5-0.6 years in girls and 0.3- 0.4 years in boys (‘persistent’). At one year, more girls than boys had breast tissue present (p=0.010). Most clinical and hormonal markers did not differ in infants with/without persistent breast tissue. However, in those with persistent breast tissue, estradiol (first visit, girls, p=0.034), androstenedione, corticosterone, cortisol (first visit, boys, all p<0.050), length (first visit, boys, p=0.030), and testicular volume (0.3-0.4 years, p=0.040) were higher, while IGF-I (0.3-0.4, boys, p=0.033) was lower. In boys, a combined, PCA-derived hormone profile (first visit) was able to predict the persistence of breast tissue (area under the curve=83%) better than any single marker. Discussion: Palpable breast tissue in infancy is common in both sexes although it persists in significantly more girls than boys at one year of age. Data supports both the early origin of breast tissue (in utero- and early postnatal) as well as a role of endogenous hormone production in later development and maintenance. [ABSTRACT FROM AUTHOR]

Objective: Little is known about the ratio between luteinizing hormone (L H) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants. Design: A prospective, longitudinal cohort study of healthy infants ag ed 0-1.2 years. Methods: In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials. gov ID: NCT02784184), with 567 serum and 603 urine samples, wer e included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the a bility of LH/FSH to detect sex in healthy infants. Results: In both serum and urine, LH/FSH was highest in males with mini mal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging fr om 93 to 100% with correspondingly narrow 95% CIs. Conclusions: Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the rat io remain to be elucidated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Principal component analysis (PCA) is a mathematical model which simplifies data into new, combined variables. Optimal treatment of pediatric congenital adrenal hyperplasia (CAH) remains a challenge and requires evaluation of all biochemical and clinical markers. The aim of this study was to introduce PCA methodology as a tool to optimize management in a cohort of pediatric and adolescent patients with CAH by including adrenal steroid measurements and clinical parameters. Methods: This retrospective, longitudinal cohort of 33 children and adolescents with CAH due to 21-hydroxylase deficiency included 406 follow-up observations. PCAs were applied to serum hormone concentrations and compared to treatment efficacy evaluated by clinical parameters. Results: We provide and describe the first PCA models with hormone parameters denoted in sex- and age-adjusted standard deviation (SD) scores to comprehensibly describe the combined 'endocrine profiles' of patients with classical and non-classical CAH, respectively. Endocrine profile scores were predictive markers of treatment efficacy for classical (AUC=92%; accuracy 95%; p=1.8e-06) and non-classical CAH (AUC=80%; accuracy 91%; p=0.004). A combined PCA demonstrated clustering of patients with classical and non-classical CAH by serum 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone-sulphate (DHEAS) concentrations. Conclusion: As an example of the possibilities of PCA, endocrine profiles were successfully able to distinguish between patients with CAH according to treatment efficacy and to elucidate biochemical differences between classical and non-classical CAH. [ABSTRACT FROM AUTHOR]

Objective: Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism. Methods: Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression. Results: Serum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed. Conclusions: In this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3. [ABSTRACT FROM AUTHOR]

Purpose: Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC–MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS). Methods: This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC–MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated. Results: In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01). Conclusions: The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear. [ABSTRACT FROM AUTHOR]

Background: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex.Main Body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate.Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data. [ABSTRACT FROM AUTHOR]

Background: Accurate and selective assessment of testosterone requires use of a sensitive LC-MS/MS method, especially at low levels as those seen in young children. Methods: The present longitudinal study of 20 healthy children from the Copenhagen Puberty Study followed every 6 months for 5 years evaluates the longitudinal increase in serum testosterone before, during and after pubertal onset quantified by a newly developed LC-MS/MS method in comparison with immunoassay. Testosterone concentrations in serum samples (n = 177) were determined by LC-MS/MS (detection limit 0.1 nmol/l) and by immunoassay (detection limit 0.23 nmol/l). Results: Serum concentrations of testosterone increased gradually with age by both methods. However, serum testosterone was quantifiable in 9/10 girls prior to pubic hair development measured with LC-MS/MS, and in 2/10 girls measured with immunoassay. In boys, testosterone was quantifiable in 10/10 boys 1 year prior to pubic hair development measured with LC-MS/MS, and only in 1/10 boys measured with immunoassay. Serum testosterone levels were quantifiable 1.5 years (range 0.5-2.5) earlier using LC-MS/MS. Conclusion: Assessment of longitudinal circulating levels of serum testosterone using a selective LC-MS/MS method proved to be more sensitive in predicting early peripubertal changes in healthy children compared to levels determined by immunoassay. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid metabolism, and shown to be elevated in diseases related to metabolic syndrome. Due to the increasing frequency of metabolic syndrome in the pediatric population, and as FGF21 studies in children are limited, we investigated baseline serum levels of FGF21 in healthy children during an oral glucose tolerance test. Methods A total of 179 children and adolescents from the COPENHAGEN Puberty Study were included. An OGTT with glucose and insulin measurements, a dual energy X-ray absorptiometry (DXA) scan and a clinical examination including pubertal staging were done on all subjects. Serum levels of FGF21, adiponectin, and leptin were determined by immunoassays at baseline. Results The girls had significantly higher levels of FGF21 compared with boys (155 pg/mL vs. 105 pg/mL, P = 0.04). 38 children (21%) had levels below detection limit of assay. Baseline levels of FGF21 showed positive correlation with triglycerides, but no significant correlations were found between FGF21-concentration and body mass index (BMI), DXA-derived fat percentage, LDL- HDL- and non-HDL cholesterol, leptin or adiponectin levels, respectively. Neither was any correlation found between baseline FGF21-levels and the dynamic changes in glucose and insulin levels during the OGTT. Conclusion FGF21 is independent of adiposity in children, and the significant metabolic effect seems to be limited to pathological conditions associated with insulin resistance. The higher levels of triglycerides in the girls may explain the significantly higher levels of FGF21 in girls compared with boys. [ABSTRACT FROM AUTHOR]

Insulin-like factor 3 (INSL3) is a promising marker of Leydig cell function with potentially high clinical relevance. Limited data of INSL3 levels in relation to other reproductive hormones in healthy pubertal boys exist. In this study, we aimed to evaluate longitudinal serum changes in INSL3 compared with LH, FSH, testosterone, inhibin B, and anti-Müllerian hormone (AMH) during puberty in healthy boys. Ten boys were included from the longitudinal part of the COPENHAGEN Puberty Study. Pubertal evaluation, including testicular volume, was performed and blood samples were drawn every 6 months for 5 years. Serum concentrations of testosterone were determined by a newly developed LC-MS/MS method, and serum concentrations of INSL3, AMH, inhibin B, FSH, and LH respectively were determined by validated immunoassays. The results showed that serum INSL3 levels increased progressively with increasing age, pubertal onset, and testicular volume. In six of the ten boys, LH increased before the first observed increase in INSL3. In the remaining four boys, the increase in LH and INSL3 was observed at the same examination. The increases in serum concentrations of LH, testosterone, and INSL3 were not parallel or in ordered succession and varied interindividually. We demonstrated that INSL3 concentrations were tightly associated with pubertal onset and increasing testicular volume. However, the pubertal increases in LH, INSL3, and testosterone concentrations were not entirely parallel, suggesting that INSL3 and testosterone may be regulated differently. Thus, we speculate that INSL3 provides additional information on Leydig cell differentiation and function during puberty compared with traditional markers of testicular function. [ABSTRACT FROM AUTHOR]

Using measurements of circulating anti-Müllerian hormone (AMH) in diagnosing and managing reproductive disorders in pediatric patients requires thorough knowledge on normative values according to age and gender.We provide age- and sex-specific reference ranges for the Immunotech assay and conversion factors for theDSL andGeneration II assays.With this tool in hand, the pediatrician can use serum concentrations of AMH when determining the presence of testicular tissue in patients with bilaterally absent testes or more severe Disorders of Sex Development (DSD). Furthermore, AMH can be used as a marker of premature ovarian insufficiency (POI) in both Turner Syndrome patients and in girls with cancer after treatment with alkylating gonadotoxic agents. Lastly, its usefulness has been proposed in the diagnosis of polycystic ovarian syndrome (PCOS) and ovarian granulosa cell tumors and in the evaluation of patients with hypogonadotropic hypogonadism. [ABSTRACT FROM AUTHOR]

Objective To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome. Setting Tertiary paediatric endocrine centre. Methods Retrospective evaluation of 14 male patients with partial androgen insensitivity syndrome (PAIS) with verified androgen receptor (AR) mutations. The authors recorded phenotypic characteristics at birth and external masculinisation score (EMS), registered longitudinal growth, circulating levels of testosterone, estradiol, luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin-B and sex hormone binding globulin (SHBG), in addition to phenotype at postpubertal follow up. Results The EMS ranged from 5 to 12 in PAIS at birth. Six patients were born with hypospadias and all patients developed gynaecomastia in puberty. Eight of the patients received testosterone treatment. At follow-up penile size was impaired irrespective of EMS at birth, but responded to pubertal androgen therapy in some of the patients. Serum levels of testosterone, estradiol, SHBG and LH, but not FSH and inhibin B, were markedly elevated in puberty. Final height was 181.3 cm (165.7- 190.5 cm) corresponding to an SD score of 0.7 (-2.1 to +2.1 SD, n=10). Conclusion Gynaecomastia and impaired phallic growth are frequently observed in adults with PAIS, but may be ameliorated by androgen therapy. The authors suggest that male patients presenting with gynaecomastia in puberty, and elevated circulating levels of testosterone, estradiol and LH in puberty, but normal FSH, should be suspected of having PAIS and undergo genetic testing for AR mutations. [ABSTRACT FROM AUTHOR]