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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]

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]

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]