Ninnie Helen Bakken Oehme

Context Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age. Objective We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI). Methods Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established “LMS” growth chart algorithm in R. Results Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (β = 0.5, P < 0.001) and leptin (β = 0.6, P < 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (β = −0.4, P < 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class. Conclusion Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.

Background: Previous studies investigating the association between weight status and onset of puberty in boys have been equivocal. It is currently unclear to what extent weight class influences puberty onset and progression.Objectives: To explore the relationship between degree of sexual maturation and anthropometric measures in Norwegian boys.Methods: The following endpoints were collected in a Norwegian cross‐sectional study of 324 healthy boys aged 9–16: ultrasound‐determined testicular volume (USTV), total serum testosterone, Tanner pubic hair stage, height, weight, waist circumference (WC), subscapular skinfolds (SSF), and body fat percentage (%BF). Testicular volume‐for‐age z‐scores were used to classify “early,” “average,” or “late” maturing boys. Ordinal logistic regression analyses with a proportional odds model were applied to analyze the association between anthropometric variables and age‐adjusted degree of pubertal development, with results expressed as age‐adjusted odds ratios (AOR). Cumulative incidence curves for reaching pubertal milestones were stratified by BMI.Results: Boys with a low BMI for age (BMI_z < −1) were less likely to have reached a pubertal testicular volume (USTV ≥ 2.7 mL) or a pubertal serum level of testosterone (≥0.5 nmol/L) compared to normal weight boys (AOR 0.3, p = 0.038, AOR 0.3, p = 0.026, respectively), and entered puberty on average with a delay of approximately eight months. Boys with high BMI for age (BMI_z > 1) exhibited a comparable timing as normal weight boys. The same was found for WC. Pubertal markers were not associated with SSF or %BF.Conclusion: By examining the association between puberty and weight status classified as low, average, or high, we found that a low BMI or WC for age were associated with a less advanced pubertal development and delayed timing of puberty in boys. No significant association was observed for a high BMI or WC. Moreover, no significant effects of SSF or %BF were observed. A low weight status should also be considered when assessing pubertal development in boys.

Context Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset. Objective To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche. Design Setting and Participants Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years. Main Outcome Measures Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E₂) and estrone (E₁) from the subpicomolar range. Results References for E₂, E₁, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P < 0.001). Ultrasound detection of nonpalpable glandular tissue in 14 out of 264 (5.3%) girls with clinically prepubertal presentation was associated with significantly higher median serum levels of E₂ (12.5 vs 4.9 pmol/L; P < 0.05) and a distinct endocrine profile (arbitrary units; P < 0.001). Conclusions We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset.

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Aim To estimate references for testicular volume measured with ultrasound and Tanner stages of pubic hair in Norwegian boys, and to compare the timing of puberty with data from similar populations. Methods Testicular volume was derived from ultrasound measurements of testicular volume in a cross‐sectional study of 514 healthy boys. A continuous testicular volume for age reference curve was estimated with the LMS method. Tanner stages for pubic hair were clinically assessed in 452 boys. Age references for pubertal milestones were estimated with probit regression. Results Puberty onset, defined by an ultrasound testicular volume of 2.7 ml, equivalent to an orchidometer volume of 4 ml, occurred at a mean (SD) age of 11.7 (1.1) years. The reference range was 9.7 (3^rd) to 13.7 years (97^th percentile). Pubic hair (Tanner stage 2) appeared on average at 11.8 (1.2) years with a corresponding reference range of 9.5 to 14.1 years. Conclusion The references for testicular volume measured with ultrasound are continuous in age, and allow for the quantification of pubertal development. The age distribution of reaching pubertal milestones was comparable with data from other Northern European countries.

Context: Testicular growth represents the best clinical variable to evaluate male puberty, but current pediatric hormone references are based on chronological age and subjective assessments of discrete puberty development stages. Determination of testicular volume (TV) by ultrasound provides a novel approach to assess puberty progression and stratify hormone reference intervals. Objective: The objective of this article is to establish references for serum testosterone and key hormones of the male pituitary-gonadal signaling pathway in relation to TV determined by ultrasound. Design, Setting, and Participants: Blood samples from 414 healthy Norwegian boys between ages 6 and 16 years were included from the cross-sectional “Bergen Growth Study 2.” Participants underwent testicular ultrasound and clinical assessments, and serum samples were analyzed by liquid chromatography tandem–mass spectrometry and immunoassays. Main Outcome Measures: We present references for circulating levels of total testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin in relation to TV, chronological age, and Tanner pubic hair stages. Results: In pubertal boys, TV accounted for more variance in serum testosterone levels than chronological age (Spearman r = 0.753, P < .001 vs r = 0.692, P < .001, respectively). Continuous centile references demonstrate the association between TV and hormone levels during puberty. Hormone reference intervals were stratified by TV during the pubertal transition. Conclusions: Objective ultrasound assessments of TV and stratification of hormone references increase the diagnostic value of traditional references based on chronological age or subjective staging of male puberty.

Clinical assessment of pubertal breast development using Tanner staging is subjective. This has led to the introduction of ultrasound (US), aiming for a more objective analysis. However, information regarding its reliability is lacking.

Prader orchidometry has been the standard method for evaluating testicular size. As this technique is subjective and tends to overestimate the testicular volume, ultrasound (US) has been proposed as more reliable.