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Objective: To describe the natural history of inhibin B throughout life according to sex, age, and pubertal development., Methods: Based on serum samples from 2707 healthy controls aged 0 to 80 years, sex- and age-specific reference ranges of inhibin B concentrations were constructed. Concentrations were evaluated according to pubertal development and use of oral contraceptives (OCs). Also, measurements from 42 patients with Klinefelter syndrome were included., Results: In both sexes, inhibin B concentrations were high during minipuberty, decreased in childhood, and increased significantly from Tanner stages B1 to B3 (peak: B4) in females and from G1 to G3 (peak: G3) in males. Despite variations in menstruating females, inhibin B concentrations remained relatively constant after puberty, until becoming unmeasurable at menopause. Despite a modest decrease, the inhibin B concentration in males remained relatively high from puberty onwards. At any age, males had highest concentrations. Inhibin B standard deviation (SD) scores were lower in OC-users (median SD score = -0.88) than in non-users (SD score = 0.35), p < 0.001. In patients with Klinefelter syndrome, inhibin B concentrations spanned the reference range until around 15 years of age, where they decreased to subnormal or unmeasurable levels., Conclusion: Valuable sex- and age-specific reference data for inhibin B concentrations were provided. In OC-users, decreased concentrations of inhibin B underlined the ovaries as the only place of inhibin B production. In patients with Klinefelter syndrome, the decline in inhibin B concentrations at puberty underlined the shift in regulation of inhibin B production at pubertal onset., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Endogenous sex steroids influence the pubertal growth spurt and adult height. However, the impact of puberty suppression and sex steroids on growth in transgender adolescents is sparsely studied., Aim: We investigated pubertal growth, serum IGF-I and IGFBP-3, and adult height of transgender adolescents receiving hormone therapy., Methods: Observational study of a national cohort (2016-2023) comprising 219 transgender adolescents <18 years of age. Treatment consisted of gonadotropin-releasing hormone agonist (GnRHa) combined with estradiol or testosterone (adjusted to serum concentrations between 0 and +2 standard deviations (SDs) corresponding to the gender identity)., Results: Adult height was within ±2 SD for sex assigned at birth.Most trans girls reached adult height within references of girls. For trans girls (bone age ≤15 years before treatment), a growth spurt was observed during estradiol therapy. IGF-I and height SDS declined during oral estradiol administration (-0.13 SDS per month, p=0.059, and -0.02 SDS, p=0.001, respectively). We observed significantly lower adult height compared to target height for trans girls (-2.7 cm, p=0.01), and significant differences between height SDS before treatment and at adult height (-0.35 SDS, p<0.001).Half of the trans boys remained short (<-2 SD) compared to references for boys, and most completed growth spurt before initiation of treatment. IGFBP-3 declined following testosterone treatment. There was a significant difference between height SDS before treatment and at adult height (-0.17 SDS, p<0.001)., Discussion and Conclusion: The minor reduction in adult height of trans girls after hormone treatment may be beneficial to some, whereas trans boys did not experience height gain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Little is known about the ratio between luteinizing hormone (LH) 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 aged 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, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants., Results: In both serum and urine, LH/FSH was highest in males with minimal 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 from 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 ratio remain to be elucidated.

Context: The male hypothalamic-pituitary-gonadal (HPG) axis is transiently active during the first months of life with surging serum concentrations of reproductive hormones. This period, termed minipuberty, appears to be essential for priming testicular function. Despite the central role for male reproductive function, longitudinal data on HPG axis activation in infancy is sparse., Objective: To explore the dynamics of HPG hormone activity in healthy male infants, to assess the association of HPG axis activity and testicular volume, and to establish reference curves for serum levels of reproductive hormones., Design: Prospective, longitudinal birth cohort (the COPENHAGEN Minipuberty Study, 2016-2018, 1-year follow-up)., Setting: Population-based., Patients or Other Participants: Healthy, male, term, singleton newborns were followed from birth on with repeated clinical examinations including blood sampling during a 1-year follow-up. A total of 128 boys contributed to this study, while 119 participated in the postnatal follow-up., Main Outcome Measures: Serum reproductive hormone concentrations and testicular volume., Results: Reproductive hormone concentrations showed marked dynamics during the first 6 months of age. Gonadotropins, total testosterone, and insulin-like factor 3 peaked at around 1 month of age. Inhibin B, anti-Müllerian hormone, and testicular volume peaked at around 4 to 5 months. Correlations largely recapitulated typical HPG axis pathways but also differed significantly from adult men., Conclusions: We demonstrate a temporal dissociation of Leydig and Sertoli cell activity during male minipuberty and provide reference curves for reproductive hormones., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Non-palpable testes remain a diagnostic challenge, often involving exploratory laparoscopy. We evaluated the diagnostic value of a wide range of reproductive hormones in order to distinguish between bilateral cryptorchidism and bilateral anorchia., Design: In this retrospective study, we identified and included 36 boys with non-palpable testes (20 with cryptorchidism, 3 with congenital hypogonadotropic hypogonadism (CHH), and 13 with anorchia) at first examination during childhood., Methods: Information on karyotype, phenotype, surgical results from laparoscopy, and biochemistry was retrieved from patient files. We compared serum concentrations of AMH, inhibin B, FSH, LH, testosterone, estradiol, and hCG stimulation testing in cryptorchid and anorchid boys to serum concentrations in a large, age-matched control group. Receiver-operating characteristic curves were used to determine the cut-off values of each reproductive hormone as a predictor of the presence of functional testicular tissue., Results: Concentrations of AMH in 0-1 year olds: ≥155 pmol/L and >1-15 year olds: ≥19 pmol/L, inhibin B (≥22 pg/mL and ≥4 pg/mL), FSH (≤28.9 IU/L and ≤20.3 IU/L) and hCG-induced testosterone (>1-15 year olds: ≥2 nmol/L) were significantly sensitive and specific markers in predicting the presence of functional testicular tissue in boys with non-palpable testes. In infancy, anorchid infants had significantly elevated gonadotropin levels, while CHH had low levels., Conclusion: Our findings suggest that laparoscopy may not be necessary in all boys with non-palpable testes if reproductive hormones unequivocally confirm the presence of functional testicular tissue. However, proving the absence may still be a diagnostic challenge.

Background: The peptide hormone insulin-like factor 3 (INSL3) is a marker for Leydig cell function and the clinical use of serum INSL3 measurements has been suggested by several groups., Aim: (1) To establish a reference range for liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum INSL3 in healthy boys and men; and (2) to compare the associations of serum INSL3 and testosterone (T) to pubertal stage, lifestyle factors, diurnal variation, body composition, and human chorionic gonadotropin (hCG) stimulation., Results: In a reference range based on LC-MS/MS analysis of serum from 1073 boys and men, INSL3 increased from levels close to the detection limit (0.03 µg/L) in prepubertal boys to a maximum mean level of 1.3 µg/L (95% CI, 0.9-2.7) in young men (19-40 years of age) and decreased slightly in older men (0.1 µg/L per decade). Serum T, but not INSL3, was associated with body mass index or body fat percentage and with alcohol consumption. Smoking was positively associated with serum T, but negatively associated with INSL3. There were significant diurnal variations in both INSL3 and T in men (P < 0.001), but serum INSL3 varied substantially less, compared with serum T (± 11% vs ± 26%). Mean serum INSL3 increased after hCG stimulation, but less than T (+ 17% vs + 53%). In both healthy men and in patients suspected of testicular failure, baseline serum INSL3 was more closely associated to the hCG-induced increase in serum T than baseline T itself., Conclusion: Measurement of serum INSL3 by LC-MS/MS has promise as a marker of testicular disorders., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations., Objective: To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3)., Design: LC-MS/MS method development and construction of estrogen reference ranges., Settings: Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas., Participants: Healthy participants aged 3 months to 61 years (n = 1838)., Results: An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from

Context: The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life., Objective: To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD., Design: A cross-sectional study., Setting: A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen., Patients or Other Participants: Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months., Main Outcome Measures: Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone-binding globulin (SHBG), inhibin B, anti-Müllerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio., Results: LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in girls. The LH/FSH ratio separated infant boys from girls with minimal overlap at a cutoff value of 0.32. Inhibin B and AMH concentrations were markedly higher in boys compared with girls, with minimal or no overlap. In infants with Klinefelter syndrome, 45,X/46,XY mosaicism and male phenotype, and Turner syndrome, the LH/FSH ratio matched the gender of rearing. However, infants with complete androgen insensitivity syndrome had LH/FSH ratios within the male range., Conclusions: Reference ranges for reproductive hormones and LH/FSH ratio during mini-puberty were established in this study. The classifiers that best separated sex in mini-puberty were AMH, LH/FSH ratio, and T. Use of the LH/FSH ratio may add valuable information in the workup of infants suspected of DSD.

Context: Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls., Objective: The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls., Design: This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls., Setting: The study was performed in the general community and in a tertiary referral center for pediatric endocrinology., Patients or Other Participants: Healthy girls (n = 38) aged 9.3 years (range, 5.9-11.3 years) at baseline and followed for 6.0 years (2.7-7.6 years) (2006-2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included., Main Outcome Measures: Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2-14 per girl), and genotyping of variants near MKRN3 (rs12148769 and rs12439354) was performed., Results: MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264-350 pg/mL) vs 257 pg/mL (243-273 pg/mL), corresponding to a reduction of 15% (1-27%) (P = .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r = -0.262 (P = .015) and for LH, r = -0.226 (P = .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25-333 pg/mL) vs 262 pg/mL (94-624 pg/mL) (P = .051). Genetic variants near MKRN3 did not correlate with serum levels of MKRN3., Conclusions: Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.

Context: Hepatic lipase influences metabolism of high-density lipoprotein (HDL), a risk factor for ischemic cardiovascular disease (ICD: ischemic heart disease and ischemic cerebrovascular disease)., Objective: We tested the hypothesis that genetic variation in the hepatic lipase genetic variants V73M, N193S, S267F, L334F, T383M, and -480c>t influence levels of lipids, lipoproteins, and apolipoproteins and risk of ICD., Design: For the cross-sectional study, we genotyped 9003 individuals from the Copenhagen City Heart Study; hereof were 8971 individuals included in the prospective study, 1747 of whom had incident ICD during 28 yr of follow-up. For the case-control studies, 2110 ischemic heart disease patients vs. 4899 controls and 769 ischemic cerebrovascular disease patients vs. 2836 controls, respectively, were genotyped. Follow-up was 100% complete., Results: HDL cholesterol was higher by 0.21 mmol/liter in S267F heterozygotes, by 0.06 mmol/liter in -480c>t heterozygotes, and by 0.13 mmol/liter in -480c>t homozygotes, as compared with noncarriers. These HDL increases theoretically predicted hazard ratios for ICD of 0.87 [95% confidence interval (CI) 0.84-0.90], 0.96 (95% CI 0.95-0.97), and 0.91 (95% CI 0.89-0.94), respectively; this calculation assumes that genetically elevated HDL levels confer decreased risk similar to common HDL elevations. In contrast, when all cases and controls were combined, the observed odds ratios for ICD for these three genetic variants vs. noncarriers were 1.19 (0.76-1.88), 1.04 (0.96-1.13), and 1.08 (0.89-1.30), respectively. Hazard/odds ratios for ICD in carriers vs. noncarriers of the four remaining hepatic lipase genetic variants did not differ consistently from 1.0., Conclusion: Hepatic lipase genetic variants with elevated levels of HDL cholesterol did not associate with risk of ICD.