Pubertal development in Norwegian boys : Ultrasound assessment of testicular volume, hormonal references, and association with anthropometric measurements

Background Puberty marks the transition from childhood to adulthood and is characterized by physiological and psychological changes leading to sexual maturity and reproductive function. Assessment of pubertal development in boys is challenging, due to the intimate and subjective nature of the examinations. Over the last decades, several studies have suggested a trend towards earlier puberty in boys, but data from Norway have been lacking. Up-to-date descriptive data allow to investigate secular trends and are required to define early or late puberty, both of which may impact on later health outcomes. The underlying mechanisms that influence the timing and progression of puberty are, particularly in boys, not fully elucidated. Overweight and obesity, as well as exposure to endocrine-disrupting chemicals, have been proposed as possible drivers for the trend towards earlier puberty. Aims The main aims of this study were to explore ultrasound as a reliable method for assessment of testicular volume and to establish references for the timing of pubertal development in Norwegian boys based on ultrasound-measured testicular volumes and the development of pubic hair. In addition, the study also aimed to establish references for serum levels of testosterone and other reproductive hormones in relation to ultrasound-derived testicular volumes and to examine the association between pubertal status and anthropometric measures in boys. Materials and methods This study is based on data from Bergen Growth Study 2 collected in 2016–2017. A total of 514 healthy boys aged 6–16 years were examined with ultrasound to measure the testicular volume, as well as clinically to assess for development of pubic hair according to the Tanner scale. In addition, anthropometric measurements, including height, weight, waist circumference, and subscapular skinfolds, as well as body composition, including body fat percentage, were recorded, and blood samples were collected for most of the participants. Results Results showed that ultrasound can be used to quantitate testicular volume in boys, without interference from surrounding scrotal tissue. The intra- and interobserver error was acceptable for clinical use. Prader orchidometry, compared to ultrasound, tended to overestimate smaller testicular volumes. Norwegian boys reached pubertal testicular volume at a mean (SD) age of 11.7 (1.1) years, and the onset of pubic hair development occurred, on average, at 11.8 (1.2) years. The study also found that testicular volume accounted for more variance in serum testosterone levels than chronological age, and that male pubertal hormone reference intervals benefited from stratification by testicular volume. Further, low body mass index (BMI) and small waist circumference for age, rather than high BMI and large waist circumference for age, influenced the timing of pubertal development. Boys with low BMI for age entered puberty approximately 8 months later than normal-weight or overweight boys. Conclusion This study demonstrates the usefulness and potential advantages of ultrasound as a method for evaluation of testicular volume in boys. Implementation of an ultrasound protocol has the added advantage of enabling more objective measurements on a continuous scale. In this study, the first references for clinical assessment of puberty in Norwegian boys were developed, which showed that Norwegian boys exhibited pubertal timing that is comparable with current Northern European references, and no apparent secular trend towards earlier puberty was observed over the last decades. Stratification of pubertal hormone references based on objective ultrasound assessments of testicular volume was shown to narrow the reference ranges and thus has the potential to increase the diagnostic value of traditional references based on chronological age. Finally, the study showed that low, but not high, BMI for age was associated with pubertal status, indicating that all weight classes should be taken into consideration when assessing sexual maturation in children and adolescents.Doktorgradsavhandlin

References for ultrasound staging of breast maturation, tanner breast staging, pubic hair, and menarche in Norwegian girls

Context - Discriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported. Objective - To present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche. Design, Setting, and Participants - A cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined. Main Outcome Measures - Breast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen’s kappa. Results - The median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen’s kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85–0.88). When the methods disagreed, US B was usually more advanced. Conclusion - Thelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls

Hormone references for ultrasound breast staging and endocrine profiling to detect female onset of puberty

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

Testicular ultrasound to stratify hormone references in a cross-sectional Norwegian study of male puberty

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.acceptedVersio

Reference curves for pediatric endocrinology: leveraging biomarker z-scores for clinical classifications

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-specifc 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 coeffcient 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 profles differed signifcantly between cohort subgroups stratifed by puberty phenotype and BMI weight class. <p<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 classifcation and covariate precision medicine for pediatric patients

Pubertal development in Norwegian boys : Ultrasound assessment of testicular volume, hormonal references, and association with anthropometric measurements

Background Puberty marks the transition from childhood to adulthood and is characterized by physiological and psychological changes leading to sexual maturity and reproductive function. Assessment of pubertal development in boys is challenging, due to the intimate and subjective nature of the examinations. Over the last decades, several studies have suggested a trend towards earlier puberty in boys, but data from Norway have been lacking. Up-to-date descriptive data allow to investigate secular trends and are required to define early or late puberty, both of which may impact on later health outcomes. The underlying mechanisms that influence the timing and progression of puberty are, particularly in boys, not fully elucidated. Overweight and obesity, as well as exposure to endocrine-disrupting chemicals, have been proposed as possible drivers for the trend towards earlier puberty. Aims The main aims of this study were to explore ultrasound as a reliable method for assessment of testicular volume and to establish references for the timing of pubertal development in Norwegian boys based on ultrasound-measured testicular volumes and the development of pubic hair. In addition, the study also aimed to establish references for serum levels of testosterone and other reproductive hormones in relation to ultrasound-derived testicular volumes and to examine the association between pubertal status and anthropometric measures in boys. Materials and methods This study is based on data from Bergen Growth Study 2 collected in 2016–2017. A total of 514 healthy boys aged 6–16 years were examined with ultrasound to measure the testicular volume, as well as clinically to assess for development of pubic hair according to the Tanner scale. In addition, anthropometric measurements, including height, weight, waist circumference, and subscapular skinfolds, as well as body composition, including body fat percentage, were recorded, and blood samples were collected for most of the participants. Results Results showed that ultrasound can be used to quantitate testicular volume in boys, without interference from surrounding scrotal tissue. The intra- and interobserver error was acceptable for clinical use. Prader orchidometry, compared to ultrasound, tended to overestimate smaller testicular volumes. Norwegian boys reached pubertal testicular volume at a mean (SD) age of 11.7 (1.1) years, and the onset of pubic hair development occurred, on average, at 11.8 (1.2) years. The study also found that testicular volume accounted for more variance in serum testosterone levels than chronological age, and that male pubertal hormone reference intervals benefited from stratification by testicular volume. Further, low body mass index (BMI) and small waist circumference for age, rather than high BMI and large waist circumference for age, influenced the timing of pubertal development. Boys with low BMI for age entered puberty approximately 8 months later than normal-weight or overweight boys. Conclusion This study demonstrates the usefulness and potential advantages of ultrasound as a method for evaluation of testicular volume in boys. Implementation of an ultrasound protocol has the added advantage of enabling more objective measurements on a continuous scale. In this study, the first references for clinical assessment of puberty in Norwegian boys were developed, which showed that Norwegian boys exhibited pubertal timing that is comparable with current Northern European references, and no apparent secular trend towards earlier puberty was observed over the last decades. Stratification of pubertal hormone references based on objective ultrasound assessments of testicular volume was shown to narrow the reference ranges and thus has the potential to increase the diagnostic value of traditional references based on chronological age. Finally, the study showed that low, but not high, BMI for age was associated with pubertal status, indicating that all weight classes should be taken into consideration when assessing sexual maturation in children and adolescents

Low BMI, but not high BMI, influences the timing of puberty in boys

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 (BMIz 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

Low BMI, but not high BMI, influences the timing of puberty in boys

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 (BMIz 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

Reference data for testicular volume measured with ultrasound and pubic hair in Norwegian boys are comparable with Northern European populations

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 (3rd) to 13.7 years (97th percentile). Pubic hair (Tanner stage 2) appeared on average at 11.8 (1.2) years with a corresponding reference range of 9.5‐14.1 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