Testicular Ultrasound to Stratify Hormone References in a Cross-Sectional Norwegian Study of Male Puberty

Madsen, André; Oehme, Ninnie Helén Bakken; Roelants, Mathieu; Bruserud, Ingvild Særvold; Eide, Geir Egil; Viste, Kristin; Bjerknes, Robert; Almås, Bjørg; Rosendahl, Karen; Sagen, Jørn V.; Júlíusson, Pétur Benedikt

doi:10.1210/clinem/dgz094

Cited by 20 publications

(24 citation statements)

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“…This, in turn, enabled the calculation of age‐adjusted z ‐scores for each study participant in accordance with our previously published reference chart 26 . We have previously shown that the USTV of 2.7 mL immediately precedes a drastic surge in testosterone levels 35 and our current findings for the associations between testicular volume and anthropometric measurements were corroborated by equivalent findings with regard to serum testosterone. This highlights the co‐occurrence of testicular enlargement and testosterone production.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2021

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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) 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 (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.

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Section: Discussionsupporting

confidence: 87%

“…Blood samples from 299 (92.3%) boys were collected between 0800 and 1400 h and processed according to a protocol for blood sampling and analysis that was previously described 35 . Total testosterone was assayed by LC‐MS/MS as described previously 36 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…Hormone z-scores were interpolated from the “Bergen Growth Study 2” references for male [ 35 ] and female [ 36 ] hormones rendered by the generalized additive model for location, scale and shape (GAMLSS) package in R (R Core Team, Vienna, Austria). Briefly, the LMS method for normalized growth standards [ 37 ] enables the calculation of z-scores for new observations in relation to the smooth (L), mean (M) and coefficient of variation (S) curves.…”

Section: Methodsmentioning

confidence: 99%

Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

et al. 2021

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Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

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“…Justified partitioning criteria were met if the numeric Harris-Boyd z-score exceeded that of the critical z* sample power test, as mathematically outlined previously ( 26-29 ). Continuous hormone reference intervals in relation to chronological age were generated using the CLSI-compliant referenceIntervals package in R (R Development Core Team, Vienna, Austria), based on a moving window of 120 observations as described previously ( 29 ).…”

Section: Methodsmentioning

confidence: 99%

Hormone References for Ultrasound Breast Staging and Endocrine Profiling to Detect Female Onset of Puberty

Madsen

Bruserud

Bertelsen

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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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. Further, 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, age 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 sub-picomolar range. Results References for E2, E1, LH, FSH and SHBG were constructed in relation to chronological age, Tanner and US breast stages. An endocrine profile index score derived from principle component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with ROC AUC 0.91 (P<0.001). Ultrasound detection of non-palpable 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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Testicular Ultrasound to Stratify Hormone References in a Cross-Sectional Norwegian Study of Male Puberty

Cited by 20 publications

References 31 publications

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

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

Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

Hormone References for Ultrasound Breast Staging and Endocrine Profiling to Detect Female Onset of Puberty

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