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Context: The use of testosterone enanthate (TE), 50-75 mg intramuscularly (i.m.)/month, for the treatment of boys with delayed puberty or slow progression to induce puberty is the standard of care (SoC) in Sweden. This treatment is empirical and has not been scientifically evaluated. Replacement therapy in hypogonadal boys/young men in Sweden after induction is mainly performed with testosterone undecanoate (TU), 1,000 mg/3 months. TE is only available on license. TE was deregistered in Sweden in 2006. Therefore, this study was initiated to compare the two products. Objective: To clinically evaluate pubertal progression with six injections of TE, 75 mg i.m./month (1/3-1/5 of adult dose), compared with two injections of TU, 250 mg i.m./3 months (1/4 of adult dose). Trial design: In the Pubertal Replacement in Boys Study (PRIBS), boys aged 14-16 years in West Sweden with pubertal delay were randomized in a parallel study to TE or TU for pubertal progression. Inclusion criteria were morning testosterone levels of 0.5-3 nmol/L and testicular volume =6 ml. Between June 2014 and Nov 2019, 27 boys were included. Methods: The primary outcome was testicular enlargement =8 ml after 12 months. TU treatment was considered clinically similar if the number of boys with testicular enlargement =8ml was 80%-125% of the number of boys with TE. Fisher's exact chi-square test was used for this analysis. Results: Both treatments were well tolerated. Twelve of 14 (86%) TU-treated boys reached the primary outcome and 12/12 in the TE group. Fisher's exact chisquare testing indicated a one-sided p-value of 0.28 (the two-sided p-value was 0.483). The TU treatment was considered not clinically different from SoC. A post-hoc study showed 25% power. Therefore, no evidence-based conclusion can be drawn from the results even if the clinical data support a similar effect of the treatments. Conclusion: The present small-scale study supports that both TE and TU had similar effects in terms of pubertal progression. [ABSTRACT FROM AUTHOR]

Abstract Background The role of estrogens in male physiology has become evident. However, clinically useful normative data for estradiol secretion in boys has not previously been established due to the insensitivity of current methods used in clinical routine. By use of a validated ultra-sensitive extraction RIA, our aim was to establish normative data from a group consisting of healthy boys in prepuberty and during pubertal development. Methods Sixty-two 24-hours serum profiles (6 samples/24 hours) were obtained from 44 healthy boys (ages; 7.2–18.6 years) during their pubertal development, classified into five stages: prepuberty (testis, 1–2 mL), early (testis, 3–6 mL), mid (testis, 8–12 mL), late-1 (testis,15–25 mL, not reached final height) and late-2 (testis,15–25 mL, reached final height). Serum estradiol was determined by an ultra- sensitive extraction radioimmunoassay with detection limit 4 pmol/L and functional sensitivity 6 pmol/L. Results Mean estradiol concentrations during 24-hours secretion increased from prepuberty (median: Conclusion With the use of an ultra-sensitive extraction RIA, we have provided clinically useful normative data for estradiol secretion in boys.

Background: Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. Methods: The EFGCP Children's Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. Results: Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. Conclusion: Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines. [ABSTRACT FROM AUTHOR]

Objective: The aim of this work was to investigate the prevalence of premature thelarche (PT) in 18-month-old girls, and the incidence of clinically evaluated PT for girls aged 18–36 months. Methods: In the prevalence substudy, a prospective population-based cohort of 3,140 girls born at Northern Älvsborg county hospital (NÄL) in Trollhättan, Sweden, was followed for 2 years. Girls with breast development at the 18-month health check were referred to one pediatric center in NÄL for evaluation. All girls with PT were included and followed for clinical outcome and 17β-estradiol. The prospective incidence substudy covered 8 years in a 10-year period and included all girls aged 18–36 months born at NÄL who were clinically evaluated for PT. Results: The prevalence of PT at 18 months in our cohort was 1.6/1,000. The 5 girls with PT no longer showed symptoms at the follow-up 3–6 months later. The incidence was 1.1/1,000 for girls aged 18–36 months and 1.0/1,000 for girls aged 18–30 months who were clinically evaluated for their PT. Conclusion: This is the first prospective population-based study of PT and it shows a prevalence of PT at age 18 months of 1.6/1,000. The incidence of clinically evaluated PT was 1.1/1,000. Our result is in line with other studies reporting the incidence of PT from medical records (0.4–40/1,000). The outcome of PT in our study, as in the other studies, is that the great majority of girls show only benign symptoms. [ABSTRACT FROM AUTHOR]

Background: Early onset of breast development in a young girl is usually a benign and isolated prepubertal condition, i.e., premature thelarche (PT), but can sometimes be progressive and the first sign of pubertal precocity (PP). Serum 17β-estradiol (17β-E2) level is a possible marker to differentiate between benign and pathological forms of breast development. We defined an upper serum 17β-E2 level for benign, “classic” PT for girls aged 9–48 months. Methods: Serum 17β-E2 was analysed with a highly sensitive extraction radioimmunoassay (RIA). Gonadotropins, Tanner breast stage, growth, other investigations, and clinical outcome were assessed in 125 girls with breast development, in a population-based study in West Sweden. Results: A total of 125 of 128 girls had a benign form of breast development with a mean serum 17β-E2 level of 15.2 pmol/L and a mean + 2 SD of 31 pmol/L, which was regarded as the upper limit for benign PT; 3 girls with PP had 17β-E2 levels above 70 pmol/L. Conclusion: This is the first study to define an upper serum 17β-E2 level associated with benign PT. Girls aged 9–48 months with PT and Tanner breast stage 2 have 17β-E2 levels below 32 pmol/L using extraction RIA. LH below the detection limit (0.1 IU/L) and measurable FSH support benign PT. [ABSTRACT FROM AUTHOR]

Aims: We studied whether first morning voided (FMV) urinary gonadotropin measurements could be used as a noninvasive alternative to the GnRH test in the assessment of the hypothalamic-pituitary-gonadal function in children. Methods: In a single-center study, we compared FMV urinary gonadotropin concentrations with basal and GnRH-stimulated serum gonadotropin levels in 274 children and adolescents (78 girls, 196 boys) aged 5-17 years referred for growth and pubertal disorders. The concordance between FMV urinary gonadotropin concentrations and GnRH test results was assessed. Results: FMV urinary LH (U-LH), urinary FSH (U-FSH) and their ratios correlated well with the corresponding basal and GnRH-stimulated serum parameters (r = 0.66, p < 0.001). Receiver operating characteristic curve analyses using urinary and serum LH and FSH concentrations showed that FMV U-LH and U-LH/U-FSH performed equally well as the GnRH test in the differentiation of early puberty (Tanner stage 2) from prepuberty (Tanner stage 1) (area under the curve 0.768-0.890 vs. 0.712-0.858). FMV U-LH and U-LH/UFSH performed equally well as basal serum LH in predicting a pubertal GnRH test result (area under the curve 0.90-0.93). Conclusion: FMV U-LH determination can be used for the evaluation of pubertal development and its disorders, reducing the need for invasive GnRH stimulation tests. [ABSTRACT FROM AUTHOR]

Background. Immunoassays have been criticized for poor accuracy at low testosterone concentrations. Mass spectrometry (MS) has been proposed as the only reliable method for testosterone determination. The aim of this study was to compare a sensitive testosterone radioimmunoassay (RIA) with results from different MS. Methods. We compared testosterone concentrations determined by a sensitive testosterone RIA, lower limit of detection 0.03 nmol/L and limit of quantitation 0.1 nmol/L, with four tandem MS that were included in an international external quality assessment program for laboratory medicine. We also compared the morning concentrations of testosterone in girls and boys at different pubertal stages, using results from the RIA, with reported values determined by LC-MS/MS, developed for androgen determination in children. Results. The mean (SD), concentrations were similar between RIA and MS: 1.5 (0.3) and 1.4 (0.4) in the child/women range (0.8-2.6 nmol/L) and 16.0 (3.7) and 17.8 (4.5) nmol/L for the adult male range (10.1-30.0 nmol/L), respectively. The ratio between RIA and MS versus results from mean values of the four MS methods was 1.0 (0.18); 1.1 (0.18) for child/women concentrations and 0.9 (0.13) for male testosterone concentrations. Furthermore, compared to the pediatric reference values determined by LC-MS/MS, the sensitive testosterone RIA delivered similar testosterone values across the different pubertal stages. Conclusions. The comparison between different tandem MS methods and a sensitive testosterone RIA illustrates that there are immunoassays that deliver clinically useful information in prepubertal and pubertal children. [ABSTRACT FROM AUTHOR]

Background/Aim: The goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to achieve the endocrine milieu similar to natural puberty, where transdermal administration is the most physiological route. The aim of the study was to evaluate guidelines for the induction of puberty with transdermal estradiol (E2) patches in a large outpatient setting. Methods: In a retrospective study, serum E2 levels from 18 clinics were analyzed at the Göteborg Pediatric Growth Research Center laboratory, as part of the initiation of ERT in girls with hypogonadism. Exclusion criteria were pubertas tarda and pubertal arrest. Eighty-eight observations (50 with Turner syndrome, TS) were included. Serum E2 levels were determined by extraction + radioimmunoassay (detection limit 4 pmol/l) and analyzed in relation to the dose of Evorel® (25 µg/24 h, containing 1.60 mg estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium). Results: There was a linear relationship between serum E2 and the weight-based dose, with r = 0.56, p < 0.0001 for all observations and r = 0.59, p < 0.0001 for the TS study group. Linear regression analysis for doses of 0.05-0.07 µg/kg resulted in serum levels of 17-23 pmol/l (TS 17-24 pmol/l) and doses of 0.08-0.12 µg/kg in 26-39 pmol/l (TS 27-39 pmol/l). Conclusions: For the initiation of ERT with nocturnally administered E2 patches, we recommend reduced starting doses of 0.05-0.07 µg/kg, with the goal of mimicking E2 levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can still be 0.08-0.12 µg/kg. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: To study serum testosterone and estradiol in healthy boys in relation to growth during puberty up to peak height velocity (PHV). Methods: Growth velocity was analyzed through testosterone (n = 41) and 17β-estradiol (n = 37) 24-hour profiles in a dose-response model. Participants were 26 healthy boys admitted for short or tall stature or participating as healthy volunteers at the Queen Silvia Children's Hospital. Other inclusion criteria included the following: gestational age 37-42 weeks, birth weight and length >-2 standard deviation score (SDS) and prepubertal height and weight within ±3 SDS. Testosterone was measured using a modified radioimmunoassay (RIA) with a detection limit of 0.03 nmol/l. Estradiol was determined using an ultrasensitive extraction RIA with a detection limit 4 pmol/l. A sixth-grade polynomial was fitted to each child's growth data, giving growth velocity and age at PHV. Results: Growth velocity increased by 50% from prepubertal growth to PHV at a morning testosterone level of 3.1 nmol/l (95% confidence interval 2.4-4.2), EC50. The corresponding EC50 of 17β-estradiol was 6.5 pmol/l (3.2-13). Boys approaching PHV (<4% remaining) had morning testosterone levels >10 nmol/l and 17β-estradiol >9 pmol/l. Conclusion: Observed early puberty/initial mid puberty morning testosterone levels of 2.4-4.2 nmol/l are associated with a 50% increase in growth velocity from prepubertal growth to PHV in healthy boys. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Age at adiposity rebound (AR) is associated with obesity and Type 2 Diabetes in adults. The aim of the present study was to investigate the role of age at AR in adult fat mass, fat distribution and pubertal timing for a Swedish cohort. Patients and Methods: This is a retrospective cohort study. Detailed growth charts were retrieved for the men participating in the population-based GOOD (Gothenburg Osteoporosis and Obesity Determinants) study (n = 573). Body composition was analysed using dual X-ray absorptiometry and computed tomography at 18-20 years of age. Age and BMI at AR were calculated using pediatric growth charts and AR was defined as the lowest BMI between 3 and 9 years of age. Results: Subjects were divided into early (age at AR below 5.4 years of age), middle (age at AR 5.4 to 6.8 years of age) and late (age at AR after 6.8 years of age) age at AR tertiles. Subjects in the early age at AR tertile had higher young adult BMI (+8%), whole body fat mass (+34%) and amount of subcutaneous adipose tissue (+61%) than the subjects in the middle and late tertiles (p,0.01). The early age at AR tertile had an increased risk of obesity (Odds Ratio 4.1 [95% CI 1.2-13.9]) compared with the middle and late tertiles. In addition, the early age at AR tertile had Peak Height Velocity (PHV) 7 months earlier than the late tertile. Conclusions: Early age at AR was associated with young adult obesity as a consequence of a high amount of subcutaneous adipose tissue in men. In addition we made the novel observation that early age at AR was associated with an early puberty in men. [ABSTRACT FROM AUTHOR]

Aim: The objective of this study was to determine estradiol levels and assess their relationship to pubertal growth in girls. Methods: Thirty-seven 24-hour profiles of serum 17β-estradiol were retrospectively analyzed in relation to growth in 27 healthy girls admitted for short/tall stature (n = 20) or recruited as healthy volunteers at Göteborg Pediatric Growth Research Center (GP-GRC). Inclusion Criteria: Birth weight and length above -2 SDS, gestational age 37-42 weeks, prepubertal height and weight within ±3 SDS and normal growth hormone secretion. Serum estradiol was determined by a validated ultrasensitive extraction radioimmunoassay (detection limit 4 pmol/l). A sixth-grade polynomial was fitted to each girl's growth data. Growth velocity and age at peak height velocity (PHV) was calculated. Results: A dose-response model was used to find the morning 17β-estradiol level at which half of the maximal pubertal growth up to PHV had occurred, EC50, which was 20 pmol/l with a 95% confidence interval of 13-31. When 17β-estradiol exceeds early pubertal levels (Tanner breast stage 2, 10-51 pmol/l), less than 25% of the potential pubertal growth velocity up to PHV remains. Conclusions: Morning 17β-estradiol in the low early pubertal range (13-31 pmol/l) is associated with increasing growth velocity. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The role of estrogens in male physiology has become evident. However, clinically useful normative data for estradiol secretion in boys has not previously been established due to the insensitivity of current methods used in clinical routine. By use of a validated ultra-sensitive extraction RIA, our aim was to establish normative data from a group consisting of healthy boys in prepuberty and during pubertal development. Methods: Sixty-two 24-hours serum profiles (6 samples/24 hours) were obtained from 44 healthy boys (ages; 7.2-18.6 years) during their pubertal development, classified into five stages: prepuberty (testis, 1-2 mL), early (testis, 3-6 mL), mid (testis, 8-12 mL), late-1 (testis,15-25 mL, not reached final height) and late-2 (testis,15-25 mL, reached final height). Serum estradiol was determined by an ultra- sensitive extraction radioimmunoassay with detection limit 4 pmol/L and functional sensitivity 6 pmol/L. Results: Mean estradiol concentrations during 24-hours secretion increased from prepuberty (median: <4 (5-95 percentiles: <4 - 7) pmol/L) to early puberty (6 (<4 - 12 pmol/L) but then remained relatively constant until a marked increase between mid-puberty (8 (4 - 17) pmol/L) and late-1 (21 (12 - 37) pmol/L) puberty, followed by a slower increase until late-2 puberty (32 (20 - 47) pmol/L). The diurnal rhythm of serum estradiol was non-measurable in pre- and early puberty, but discerned in mid-puberty, and become evident in late pubertal stages with peak values at 0600 to 1000 h. Conclusion: With the use of an ultra-sensitive extraction RIA, we have provided clinically useful normative data for estradiol secretion in boys. [ABSTRACT FROM AUTHOR]

Conflicting results have been reported of the long-term effects of treatment with inhaled corticosteroids (ICS) on bone. The objective of this study was to compare ICS users and non-users regarding bone mineral density (BMD) in a large population. A total of 65 225 adults participated in a cross-sectional study in the Nord-Trøndelag Health Study 1995-1997. Those reporting asthma or asthma-related symptoms, were invited to have bone densitometry of the forearm, flow volume spirometry and a personal interview. Altogether 4482 women and 4142 men participated, of whom 2113 reported ever use and 6511 never use of ICS. Never-users of corticosteroids had a mean BMD, adjusted for confounders (age, square age, sex, body mass index, height, physical activity, work load, packyears, family history of osteoporosis and in women number of years since menopause and use of hormone replacement therapy), of 0.493 g/cm2 at the distal site. Subjects having only used ICS or combined with courses of prednisolone, had 0.008 g/cm2 (95%CI: 0.005-0.011) lower BMD whilst users of prednisolone ≥6 months had 0.038 g/cm2 (0.021-0.055) lower level. No dose response association between ICS and BMD, or difference in BMD by type of ICS was found. The association between CS use and BMD was independent of the measuring site. ICS use was associated with lower BMD. The lack of dose response in this study might be due to a narrow dose range or indicates that other characteristics of the patient group are contributing to the observed difference in ICS users compared to never-users. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3–17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3–15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement, written by Thomas Severin et al. was originally published electronically on the publisher's internet portal on February 6, 2020 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on April 22, 2020 to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate the pharmacodynamics, pharmacokinetics and safety of the glucokinase activator AZD6370 after 1day of administration under fed and fasted conditions in patients with type 2 diabetes mellitus (T2DM). Methods: This was a two-part study. In Part A, patients received a single oral dose of AZD6370 (20, 60 or 180mg) or placebo in the fasted or fed states (both n =8). In Part B, patients (n =8) received placebo and a total dose of AZD6370 180mg given in one, two or four divided doses. Plasma glucose, insulin and C-peptide changes versus placebo were assessed. Results: AZD6370 provided dose-dependent reductions in plasma glucose of up to 30% versus placebo in both fasted and fed patients (p <0.001 at 60 and 180mg doses). Insulin secretion increased with dose, but absolute increases were relatively small in the fasted versus fed state (0–4h). Dosing AZD6370 twice or four-times over 1day gave a smoother 24-h glucose profile than single-dose. AZD6370 was rapidly absorbed. Pharmacokinetics of AZD6370 were dose-independent and unaffected by food. AZD6370 was generally well tolerated. Conclusions: AZD6370 produced dose-dependent glucose reductions and increased glucose-stimulated insulin secretion in patients with T2DM. [Copyright &y& Elsevier]

Objectives: Low bone mineral density (BMD) is recognized as a potential problem in children with inflammatory bowel disease (IBD). We aimed to describe the longitudinal development of BMD in a population of Swedish pediatric patients with IBD., Methods: A total of 144 patients with IBD (93 males; 83 with ulcerative colitis [UC], 45 with Crohn disease [CD]) were examined with dual-energy x-ray absorptiometry at baseline. At follow-up 2 years later, 126 of the initial 144 patients were reexamined. BMD values are expressed as z scores., Results: Children with UC and CD had significantly lower mean BMD z scores for the lumbar spine (LS) at baseline and after 2 years. The reduction in BMD was equally pronounced in patients with UC and CD, and neither group improved their z score during the follow-up period. Furthermore, significantly lower mean BMD z scores for the LS were found at baseline in boys (-1.1 SD, ±2.7 SD, P < 0.001), but not in girls (-0.0 SD, ±3.0 SD). This finding remained unchanged at follow-up. Subanalyses of the different age groups at baseline showed the lowest BMD values in the group of patients ages 17 to 19 years in boys (mean z score for the LS 1.59 SD, ±3.1 SD) and in girls (mean z score for the LS -3.40 SD, ±3.1 SD); however, at follow-up, these patients had improved their BMD significantly (mean change z score for the LS 1.00 SD, 95% CI 0.40-1.60; 1.90 SD, 95% CI 0.60-3.20)., Conclusions: In this longitudinal study, the entire group of pediatric patients with IBD showed permanent decreases in their BMD z scores for the LS; however, our data indicate that afflicted children have the potential to improve their BMD by the time they reach early adulthood.

Background and Aim: Low bone mineral density (BMD) has recently been recognized as a potential health problem in children with inflammatory bowel disease (IBD). Our aim was to investigate the familial resemblance of BMD in pediatric patients with IBD., Patients and Methods: In this population-based study from western Sweden, we assessed 144 children with IBD, 83 with ulcerative colitis, 45 with Crohn disease, 16 with indeterminate colitis, and their parents (136 mothers and 130 fathers) with dual-energy X-ray absorptiometry (DEXA). After adjustment for sex, age, weight, height, and parental IBD, we correlated the BMD of the patients to the BMD of their mothers, fathers, and the midparent value ([mother's BMD + father's BMD]/2) at different skeletal sites and calculated the Pearson correlation coefficient (r) to evaluate the extent of familial resemblance., Results: The BMD of the children with IBD was clearly related to the BMD of their parents. The strongest correlation was found in the femoral neck with r = 0.55 (P < 0.001, 95% CI 0.41-0.66) between BMD of the children and the midparent value. The group of children with IBD had an odds ratio of 5.96 for decreased BMD (lumbar spine z score < -1 standard deviation) given that decreased BMD was diagnosed in both parents., Conclusions: We conclude that BMD in children and adolescents with IBD is significantly related to that of their parents. In a clinical setting, it may be helpful to assess the parents of children with IBD with DEXA to interpret the children's DEXA measurements.

Objective: To test the clinical usefulness of sensitive commercial immunoassays for determination of low 17beta-estradiol concentrations in children., Methods: The lower limit of detection and clinical usefulness (functional sensitivity) of three commercial estradiol immunoassays were validated by use of 500 sera from prepubertal and pubertal children and 55 pooled sera. The three immunoassays consisted of two modified direct immunoassays; one RIA (Spectria Estradiol RIA) and one time-resolved fluoroimmunoassay (AutoDELFIA Estradiol), both with increased serum volume in relation to antibody concentration and extended incubation time. In the third method, serum was purified and concentrated using diethyl ether extraction prior to measurement by the modified Spectria Estradiol RIA., Results: The lower limits of detection and clinical usefulness were 9 and 30 pmol/l for the direct RIA, 11 and 50 pmol/l for the AutoDELFIA, and 4 and 6 pmol/l for serum determined by extraction RIA. When measuring the serum pool originating from girls at breast stages 1-2, the direct RIA and AutoDELFIA resulted in significantly higher 17beta-estradiol concentrations when compared with the extraction RIA (+58 and +267%, P<0.001). We found a significant difference in 17beta-estradiol concentrations between girls at breast stages 1 (median 6 pmol/l) and 2 (median 16 pmol/l), when quantified by the extraction RIA (P<0.0001) but no difference when quantified with the direct RIA (median values 12 and 14 pmol/l respectively)., Conclusion: For determination of low serum 17beta-estradiol concentrations in children, an extraction step prior to commercial immunoassay is needed to achieve clinically useful results.